Relationship: 2769: Energy Deposition leads to Oxidative Stress

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Most evidence is derived from in vitro studies, predominately using rabbit models. Evidence in humans and mice is moderate, while there is considerable available data using rat models. The relationship is applicable in both sexes; however, males are used more often in animal studies. No studies demonstrate the relationship in preadolescent animals, while adolescent animals were used very often, and adults were used occasionally in in vivo studies. 

Key Event Relationship Description

Energy deposited onto biomolecules stochastically in the form on ionizing and non-ionizing radiation can cause direct and indirect molecular-level damage. As energy is deposited in an aqueous solution, water molecules can undergo radiolysis, breaking bonds to produce reactive oxygen species (ROS) (Ahmadi et al., 2021; Karimi et al., 2017) or directly increase function of enzymes involved in ROS generation (i.e. catalaze). Various species of ROS can be generated with differing degrees of biological effects. For example, singlet oxygen, superoxide, and hydroxyl radical are highly unstable, with short half-lives and react close to where they are produced, while species like H2O2 are much more stable and membrane permeable, meaning they can travel from the site of production, reacting elsewhere as a much weaker oxidant (Spector, 1990). In addition, enzymes involved in reactive oxygen and nitrogen species (RONS) production can be directly upregulated following the deposition of energy (de Jager, Cockrell and Du Plessis, 2017). Although less common than ROS, reactive nitrogen species (RNS) can also be produced by energy deposition resulting in oxidative stress (Cadet et al., 2012; Tangvarasittichai & Tangvarasittichai, 2019), a state in which the amount of ROS and RNS, collectively known as RONS, overwhelms the cell’s antioxidant defence system. This loss in redox homeostasis can lead to oxidative damage to macromolecules including proteins, lipids, and nucleic acids (Schoenfeld et al., 2012; Tangvarasittichai & Tangvarasittichai, 2019; Turner et al., 2002).

Evidence Supporting this KER

Overall weight of evidence: High

A large body of literature supports the linkage between the deposition of energy and oxidative stress. Multiple reviews describe the relationship in the context of ROS production (Marshall, 1985; Balasubramanian, 2000; Jurja et al., 2014), antioxidant depletion (Cabrera et al., 2011; Fletcher, 2010; Ganea & Harding, 2006; Hamada et al., 2014; Spector, 1990; Schoenfeld et al., 2012; Wegener, 1994), and overall oxidative stress (Eaton, 1994, Tangvarasittichai & Tangvarasittichain, 2019). This includes investigations into the mechanism behind the relationship (Ahmadi et al., 2021; Balasubramanian, 2000; Cencer et al., 2018; Eaton, 1994; Fletcher, 2010; Jiang et al., 2006; Jurja et al., 2014; Padgaonkar et al., 2015; Quan et al., 2021; Rong et al., 2019; Slezak et al., 2015; Soloviev & Kizub, 2019; Tian et al., 2017; Tahimic & Globus, 2017; Varma et al., 2011; Venkatesulu et al., 2018; Wang et al., 2019a; Yao et al., 2008; Yao et al., 2009; Zigman et al., 2000). 

Water radiolysis is a main source of free radicals. Energy ionizes water and free radicals are produced that combine to create more stable ROS, such as hydrogen peroxide, hydroxide, superoxide, and hydroxyl (Eaton, 1994; Rehman et al., 2016; Tahimic & Globus, 2017; Tian et al., 2017; Varma et al., 2011; Venkatesulu et al., 2018). ROS formation causes ensuing damage to the body, as ~80% of tissues are comprised of water (Wang et al., 2019a). Ionizing radiation (IR) is a source of energy deposition, it can also interact with molecules, such as nitric oxide (NO), to produce less common free radicals, including RNS (Slezak et al., 2015; Tahimic & Globus, 2017; Wang et al., 2019a). Free radicals can diffuse throughout the cell and damage vital cellular components, such as proteins, lipids, and DNA, as well as dysregulate cellular processes, such as cell signaling (Slezak et al., 2015; Tian et al., 2017). 

ROS are also commonly produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Deposition of energy can activate NOX and induce expression of its catalytic and cytosolic components, resulting in increased intracellular ROS (Soloviev & Kizub, 2019). Intracellular ROS production can also be initiated through the expression of protein kinase C, which in turn activates NOX through phosphorylation of its cytosolic components (Soloviev & Kizub, 2019). Alternatively, ROS are often formed at the electron transport chain (ETC) of the mitochondria, due to IR-induced electron leakage leading to ionization of the surrounding O2 to become superoxide (Soloviev & Kizub, 2019). Additionally, energy reaching a cell can be absorbed by an unstable molecule, often NADPH, known as a chromophore, which leads to the production of ROS (Balasubramanian, 2000; Cencer et al., 2018; Jiang et al., 2006; Jurja et al., 2014; Padgaonkar et al., 2015; Yao et al., 2009; Zigman et al., 2000). 

Energy deposition can also weaken a cell’s antioxidant defence system through the depletion of certain antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT). Antioxidants are consumed during the process of neutralizing ROS, so as energy deposition stimulates the formation of ROS it begins to outpace the rate at which antioxidants are replenished; this results in an increased risk of oxidative stress when their concentrations are low (Belkacémi et al., 2001; Giblin et al., 2002; Ji et al., 2014; Kang et al., 2020; Karimi et al., 2017; Padgaonkar et al., 2015; Rogers et al., 2004; Slezak et al., 2015; Tahimic & Globus, 2017; Wang et al., 2019a; Wegener, 1994; Weinreb & Dovrat, 1996; Zhang et al., 2012; Zigman et al., 1995; Zigman et al., 2000). When the amount of ROS overwhelms the antioxidant defence system, the cell will enter oxidative stress leading to macromolecular and cellular damage (Tangvarasittichai & Tangvarasittichai, 2019). 

The relationship between energy deposition and oxidative stress is strongly supported by primary research on the effects of IR on ROS and antioxidant levels (Bai et al., 2020; Cervelli et al., 2017; Hatoum et al., 2006; Huang et al., 2018; Huang et al., 2019; Karam & Radwan, 2019; Kook et al., 2015; Liu et al., 2018; Liu et al., 2019; Mansour, 2013; Philipp et al., 2020; Ramadan et al., 2020; Sharma et al., 2018; Shen et al., 2018; Soltani et al., 2016; Soucy et al., 2010; Soucy et al., 2011; Ungvari et al., 2013; Wang et al., 2016; Wang et al., 2019b; Zhang et al., 2018; Zhang et al., 2020). Of note is that the relationship is demonstrated across studies conducted using various cell types, models and using broad dose ranges as summarized below. Much evidence is available and described to help discern the quantitative understanding of the relationship, since it is well established.

Dose Concordance 

It is well-accepted that any dose of radiation will deposit energy onto matter. Doses as low as 1 cGy support this relationship (Tseung et al., 2014). Following the deposition of energy, markers of oxidative stress are observed in the form of RONS, a change in levels of antioxidants, and oxidative damage to macromolecules. These effects have been shown across various organs/tissues and cell types as described below. 

RONS

Cardiovascular tissue: 

There is a considerable amount of evidence to support this relationship in cell types and tissues of relevance to the cardiovascular system. Recent studies have shown a linear increase in ROS in human umbilical vein endothelial cells (HUVECs) following 0-5 Gy gamma irradiation (Wang et al., 2019b). HUVECs irradiated with 0.25 Gy X-rays (Cervelli et al., 2017) and 9 Gy 250kV photons (Sharma et al., 2018) show increased ROS. Gamma ray irradiated rats at 5 Gy display increased ROS levels in the aorta (Soucy et al., 2010). A study using cerebromicrovascular endothelial cell (CMVECs) showed a dose-dependent increase in ROS from 0-8 Gy gamma irradiation (Ungvari et al., 2013). Additionally, telomerase-immortalized coronary artery endothelial (TICAE) and telomerase-immortalized microvascular endothelial (TIME) cells irradiated with 0.1 and 5 Gy of X-rays displayed increased ROS production (Ramadan et al., 2020). Gut arterioles of rats showed increased ROS following multiple fractions of 2.5 Gy X-ray rat irradiation (Hatoum et al., 2006). Additionally, rats irradiated with 1 Gy of 56Fe expressed increased ROS levels in the aorta (Soucy et al., 2011).   

Brain tissue:  

Markers of oxidative stress have also been consistently observed in brain tissue. Human neural stem cells subjected to 1, 2 or 5 Gy gamma rays showed a dose-dependent increase in RONS production (Acharya et al., 2010). A dose-dependent increase in ROS was observed in rat brains following 1-10 Gy gamma rays (Collins-Underwood et al., 2008). Neural precursor cells exposed to 0-10 Gy of X-irradiation showed increased ROS levels (Giedzinski et al., 2005; Limoli et al., 2004). Mice brain tissue displayed increased ROS following proton irradiation (Baluchamy et al., 2012; Giedzinski et al., 2005). Neural processor cells expressed linearly increased ROS levels following doses of 56Fe (Limoli et al., 2007). A dose-dependent increase in RONS was also observed after exposure to 1-15 cGy 56Fe irradiation in mice neural stem/precursor cell (Tseng et al., 2014). Human neural stem cells exposed to 5-100 cGy of various ions demonstrated a dose-dependent increase in RONs (Baulch et al., 2015). 

Eye tissue: 

The eye is also sensitive to the accumulation of free radicals, in a state of antioxidant decline. It has been shown in human lens epithelial cells (HLECs) and HLE-B3 following gamma irradiation of 0.25 and 0.5 Gy that ROS levels are markedly increased (Ahmadi et al., 2021). Exposure to non-ionizing radiation, such as ultraviolet (UV)-B, has also led to increased ROS in HLECs and mice lenses (Ji et al., 2015; Kubo et al., 2010; Rong et al., 2019; Yang et al., 2020) 

Bone tissue: 

Rat bone marrow-derived mesenchymal stem cell (bmMSCs) irradiated with 2, 5 and 10 Gy gamma rays and murine MC3T3-E1 osteoblast cells irradiated with 2, 4, and 8 Gy of X-rays have shown a dose-dependent increase in ROS levels (Bai et al., 2020; Kook et al., 2015). Murine RAW264.7 cells and rat bmMSC irradiated with 2 Gy of gamma rays displayed increased ROS levels (Huang et al., 2019; Huang et al., 2018; hang et al., 2020). Human bone marrow-derived mesenchymal stem cell (hBMMSCs) irradiated with 2 or 8 Gy X-rays showed increased ROS (Liu et al., 2018; Zhang et al., 2018). Similarly, murine MC3T3-E1 osteoblast-like cells irradiated with 6 Gy of X-rays also displayed increased ROS (Wang et al., 2016). Finally, whole-body irradiation of mice with 2 Gy of 31.6 keV although LET 12C heavy ions showed increased ROS (Liu et al., 2019) 

Antioxidants

Blood:  

Workers exposed to X-rays at less than 1 mSv/year for an average of 15 years showed around 20% decreased antioxidant activity compared to unexposed controls (Klucinski et al., 2008). Similarly, adults exposed to high background irradiation of 260 mSv/year showed about 50% lower antioxidant activity power compared to controls (Attar, Kondolousy and Khansari, 2007). 

Cardiovascular tissue: 

Heart tissue of rats following gamma irradiation of rats at 5 and 6 Gy resulted in a decrease in antioxidant levels (Karam & Radwan, 2019; Mansour, 2013). Similarly, HUVECs (Soltani, 2016) and TICAE cells (Philipp et al., 2020) irradiated at 2 Gy and 0.25-10 Gy gamma rays, respectively, displayed decreased antioxidant levels. Mice exposed to 18 Gy of X-ray irradiation showed decreased antioxidants in the aorta (Shen et al., 2018). 

Brain tissue:  

Mice brain tissue following 2, 10 and 50 cGy whole-body gamma irradiation revealed a dose-dependent change in SOD2 activity (Veeraraghan et al., 2011). Mice brain tissue showed decreased glutathione (GSH) and SOD levels following proton irradiation (Baluchamy et al., 2012) 

Eye tissue: 

Rats exposed to 15 Gy gamma rays demonstrated decreased antioxidants in the lens tissue (Karimi et al, 2017). Neutron irradiation of rats at 3.6 Sv resulted in a decrease in antioxidants in lens (Chen et al., 2021). A few studies found a dose concordance between UV irradiation and decreased antioxidant levels (Hua et al, 2019; Ji et al, 2015; Zigman et al., 2000; Zigman et al, 1995). HLECs following UVB exposure from 300 J/m2 to 14,400 J/m2 in HLECs showed linear decreases in antioxidant activity (Ji et al., 2015). Similarly, HLEC exposed to 4050, 8100 and 12,150 J/m2 found decreased antioxidant levels (Hua et al., 2019). Following UV irradiation of rabbit and squirrel lens epithelial cells (LECs) showed a linear decrease of antioxidant level, CAT (Zigman et al., 2000; Zigman et al., 1995). Mice exposed to UV irradiation found decreased antioxidant levels in lens (Zhang et al., 2012). Similarly, SOD levels decreased following 0.09 mW/cm 2 UVB exposure of HLECs (Kang et al., 2020). 

Bone tissue: 

Rat bmMSCs irradiated with 2, 5 and 10 Gy gamma rays and Murine MC3T3-E1 osteoblast cells irradiated with 2, 4, and 8 Gy of X- rays showed a dose-dependent decrease in antioxidant levels (Bai et al., 2020; Kook et al., 2015). hBMMSCs irradiated with 8 Gy X-rays also showed a decrease in antioxidant, SOD, levels (Liu et al., 2018). 

Oxidative Damage 

Cardiovascular tissue: 

HUVECs and rat hearts irradiated by gamma rays at 2 and 6 Gy, respectively, resulted in increased levels of oxidative stress markers, such as malondialdehyde (MDA), and thiobarbituric reactive substances (TBARS) (Mansour, 2013; Soltani, 2016).  

Brain tissue:  

 Mice brain tissue were shown to have increased lipid peroxidation (LPO) as determined by MDA measurements, following proton irradiation at 1 and 2 Gy (Baluchamy et al., 2012). Neural precursor cells from rat hippocampus exposed to 0, 1, 5 and 10 Gy of X- irradiation resulted in increased lipid peroxidation (Limoli et al., 2004). 

Eye tissue: 

Rats exposed to 15 Gy gamma rays demonstrated increased MDA in lens tissue (Karimi et al, 2017). Neutron irradiation of rats at 3.6 Sv resulted in an initial decrease, followed by an increase in MDA in lens (Chen et al., 2021). Following UV irradiation at 300, 4050, 8100 and 12,150 J/m2, there was an increase in LPO in human lens (Chitchumroonchokchai et al., 2004; Hua et al., 2019). Similarly, LPO increased following 0.09 mW/cm2 UVB exposure of HLECs (Kang et al., 2020). 

Time Concordance 

It is well-accepted that deposition of energy into matter results in immediate vibrational changes to molecules or ionization events. Deposition of energy is therefore an upstream event to all follow-on latent events like oxidative stress. 

RONS

Cardiovascular tissue: 

In TICAE and TIME cells, ROS increased at 45 minutes after X-ray irradiation (Ramadan et al., 2020). Superoxide and peroxide production were increased 1 day after 2-8 Gy of gamma irradiation in CMVECs (Unvari et al., 2013). 

Bone tissue: 

hBMMSCs irradiated with X-rays at 2 Gy showed peak ROS production at 2-8h post-irradiation (Zhang et al., 2018). Murine RAW264.7 cells (can undergo osteoclastogenesis) irradiated with 2 Gy of gamma rays showed increased ROS at 2-8h post- irradiation (Huang et al., 2018). 

Brain tissue: 

In human lymphoblast cells exposed to 2 Gy of X-rays, ROS were increased at various times between 13 and 29 days post- irradiation (Rugo and Schiestl, 2004). RONS were increased in human neural stem cells at 12-48h post-irradiation with 2 and 5 Gy of gamma rays (Acharya et al., 2010). ROS levels were increased in rat neural precursor cells at 6-24h after irradiation with 1-10 Gy of protons (Giedzinksi et al., 2005). Both 56Fe (1.3 Gy) and gamma ray (2 Gy) irradiation of mice increased ROS levels after 2 months post-irradiation in the cerebral cortex (Suman et al., 2013). ROS were also increased 12 months after 56Fe irradiation (Suman et al., 2013). RONS increased as early as 12h post-irradiation continuing to 8 weeks with 2-200 cGy doses of 56Fe irradiation of mouse neural stem/precursor cells (Tseng et al., 2014). The same cell type irradiated with 1 and 5 Gy of 56Fe irradiation showed increased ROS at 6h post-irradiation, with the last increase observed 25 days post-irradiation (Limoli et al., 2004). 

Eye tissue: 

Mice exposed to 11 Gy of X-rays showed increased ROS at 9 months post-irradiation in lenses (Pendergrass et al., 2010). In human lens cells, ROS were found increased at 1h after 0.25 Gy gamma ray irradiation (Ahmadi et al., 2021), 15 minutes after 30 mJ/cm2 UV radiation (Jiang et al., 2006), 2.5-120 minutes after 0.014 and 0.14 J/cm2 UV radiation (Cencer et al., 2018), and 24h after 30 mJ/cm2 UVB-radiation (Yang et al., 2020). 

Antioxidants

Cardiovascular tissue: 

CAT antioxidant enzyme was decreased in mice aortas as early as 3 days post-irradiation, remaining decreased until 84 days after irradiation with 18 Gy of X-rays (Shen et al., 2018). The antioxidant enzymes peroxiredoxin 5 (PRDX5) and SOD were both shown to have the greatest decrease at 24h after 2 Gy gamma irradiation of TICAE cells (Philipp et al., 2020). 

Eye tissue: 

Bovine lenses irradiated with 44.8 J/cm2 of UVA radiation showed decreased CAT levels at 48-168h post-irradiation (Weinreb and Dovrat, 1996). UV irradiation of mice at 20.6 kJ/m2 led to decreased GSH at both 1 and 16 months post-irradiation in the lens (Zhang et al., 2012). Bovine lens cells exposed to 10 Gy of X-rays showed decreased levels of the antioxidant GSH at 24 and 120h after exposure (Belkacemi et al., 2001). 

Oxidative damage markers

Cardiovascular tissue: 

Oxidative damage markers 4-hydroxynonemal (4-HNE) and 3-Nitrotyosine (3-NT) were both significantly increased in the aorta of mice at 3 days post-irradiation, remaining increased until 84 days after irradiation with 18 Gy of X-rays (Shen et al., 2018). 

Essentiality 

Radiation has been found to induce oxidative stress above background levels. Many studies have shown that lower doses of ionizing radiation resulted in decreased levels in markers of oxidative stress in multiple cell types (Acharya et al., 2010; Ahmadi et al., 2021; Bai et al., 2020; Baluchamy et al., 2012 Chen et al., 2021; Collins-Underwood et al., 2008; Giedzinski et al., 2005; Kook et al., 2015; Kubo et al., 2010; Philipp et al., 2020; Ramadan et al., 2020; Ungvari et al., 2013; Veeraraghan et al., 2011; Wang et al., 2019b; Zigman et al., 2000; Zigman et al., 1995). The essentiality of deposition of energy can be assessed through the removal of deposited energy, a physical stressor that does not require to be metabolized in order to elicit downstream effects on a biological system. Studies that do not deposit energy are observed to have no downstream effects.

There are several uncertainties and inconsistencies in this KER.  

• Chen et al. (2021) found that radiation can have adaptive responses. The study used three neutron radiation doses, 0.4 and 1.2 Sv, and 3.6 Sv. After 0.4 and 1.2 Sv, the activity of antioxidant enzymes GSH and SOD increased, and the concentration of malondialdehyde, a product of oxidative stress, decreased. After 3.6 Sv, the opposite was true. 

• While the concentration of most antioxidant enzymes decreases after energy deposition, there is some uncertainty with SOD. Certain papers have found that its concentration decreases with dose (Chen et al., 2021; Hua et al., 2019; Ji et al., 2015; Kang et al., 2020) while others found no difference after irradiation (Rogers et al., 2004; Zigman et al., 1995). Several studies have also found that higher levels of SOD do not increase resistance to UV radiation (Eaton, 1994; Hightower, 1995). 

• At 1-week post-irradiation with 10 Gy of 60Co gamma rays, TICAE cells experienced a significant increase in levels of the antioxidant, PRDX5, contrary to the decrease generally seen in antioxidant levels following radiation exposure (Philipp et al., 2020). 

• Various studies found an increase in antioxidant SOD levels within the brain after radiation exposure (Acharya et al., 2010; Baluchamy et al., 2012; Baulch et al., 2015; Veeraraghan et al., 2011). 

• Chien et al. (2015) found no changes to ROS levels in hippocampal neurons five days after 0.2 Gy of electron radiation. 

• Antioxidants that increase in expression are indicative of the presence of RONS. When antioxidants decrease in expression/activity, this is most likely due to the overwhelming of the antioxidant defence mechanisms 

• There is limited data to support an understanding of deposition of energy leading to oxidative stress at low doses.

Quantitative Understanding of the Linkage

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated. 

Dose Concordance 

Time Concordance 

The relationship between deposition of energy and increased oxidative stress leads to several feedforward loops. Firstly, ROS activates the transforming growth factor beta (TGF)-β, which increases the production of ROS. This process is modulated in normal cells containing PRDX-6, or cells with added MnTBAP, which will both prevent TGF-β from inducing ROS formation (Fatma et al., 2005). Secondly, ROS can damage human mitochondrial DNA (mtDNA), this can then cause changes to the cellular respiration mechanisms, leading to increased ROS production (Turner et al., 2002; Zhang et al., 2010; Tangvarasittichai & Tangvarasittichai, 2019, Ahmadi et al., 2021; Yves, 2000). Some other feedback loops through which deposition of energy causes oxidative stress are discussed by Soloviev & Kizub (2019). 

References

Acharya, M. M. et al. (2010), “Consequences of ionizing radiation-induced damage in human neural stem cells”, Free radical biology & medicine, Vol. 49/12, Elsevier, Amsterdam,  https://doi.org/10.1016/j.freeradbiomed.2010.08.021.  

Ahmadi, M. et al. (2021), “Early responses to low-dose ionizing radiation in cellular lens epithelial models”, Radiation research, Vol. 197/1, Radiation Research Society, Bozeman, https://doi.org/10.1667/RADE-20-00284.1 

Attar, M., Y. M. Kondolousy, N. Khansari, (2007), “Effect of High Dose Natural Ionizing Radiation on the Immune System of the Exposed Residents of Ramsar Town, Iran”, Iranian Journal of Allergy, Asthma and Immunology, Vol. 6/2, pp. 73-78.   

Bai, J. et al. (2020), “Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling”, American Journal of Physiology - Cell Physiology, Vol. 318/5, American Physiological Society, Rockville, https://doi.org/10.1152/ajpcell.00520.2019. 

Balasubramanian, D (2000), “Ultraviolet radiation and cataract”, Journal of ocular pharmacology and therapeutics, Vol. 16/3, Mary Ann Liebert Inc., Larchmont, https://doi.org/10.1089/jop.2000.16.285.  

Baluchamy, S. et al. (2012), “Reactive oxygen species mediated tissue damage in high energy proton irradiated mouse brain”, Molecular and cellular biochemistry, Vol. 360/1-2, Springer, London, https://doi.org/10.1007/s11010-011-1056-2. 

Baulch, J. E. et al. (2015), “Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles Redox biology, Vol. 5, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2015.03.001. 

Belkacémi, Y. et al. (2001), “Lens epithelial cell protection by aminothiol WR-1065 and anetholedithiolethione from ionizing radiation”, International journal of cancer, Vol. 96, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/ijc.10346. 

Cabrera M., R. Chihuailaf and F. Wittwer Menge (2011), “Antioxidants and the integrity of ocular tissues”, Veterinary medicine international, Vol. 2011, Hindawi, London, https://doi.org/10.4061/2011/905153.  

Cadet, J. et al. (2012), “Oxidatively generated complex DNA damage: tandem and clustered lesions”, Cancer letters, Vol. 327, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2012.04.005.  

Cencer, C. et al. (2018), “PARP-1/PAR activity in cultured human lens epithelial cells exposed to tow levels of UVB light”, Photochemistry and photobiology, Vol. 94, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1111/php.12814.  

Cervelli, T. et al. (2017), “A New Natural Antioxidant Mixture Protects against Oxidative and DNA Damage in Endothelial Cell Exposed to Low-Dose Irradiation”, Oxidative medicine and cellular longevity, Vol. 2017, Hindawi, London, https://doi.org/10.1155/2017/9085947.  

Chen, Y. et al. (2021), “Effects of neutron radiation on Nrf2-regulated antioxidant defence systems in rat lens”, Experimental and therapeutic medicine, Vol. 21/4, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/etm.2021.9765.  

Chien, L. et al. (2015) “Low-dose ionizing radiation induces mitochondrial fusion and increases expression of mitochondrial complexes I and III in hippocampal neurons”, Oncotarget, Vol. 6/31, Impact Journals, Orchard Park, https://doi.org/10.18632/oncotarget.5790 

Chitchumroonchokchai, C. et al. (2004), “Xanthophylls and α-tocopherol decrease UVB-induced lipid peroxidation and stress signaling in human lens epithelial cells”, The Journal of Nutrition, Vol. 134/12, American Society for Nutritional Sciences, Bethesda, https://doi.org/10.1093/jn/134.12.3225.  

Collins-Underwood, J. R. et al. (2008), “NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells”, Free radical biology & medicine, Vol. 45/6, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2008.06.024.  

de Jager, T.L., Cockrell, A.E., Du Plessis, S.S. (2017), “Ultraviolet Light Induced Generation of Reactive Oxygen Species”, in Ultraviolet Light in Human Health, Diseases and Environment. Advances in Experimental Medicine and Biology, Springer, Cham, https://doi.org/10.1007/978-3-319-56017-5_2   

Demir, E. et al. (2020), “Nigella sativa oil and thymoquinone reduce oxidative stress in the brain tissue of rats exposed to total head irradiation”, International journal of radiation biology, Vol. 96/2, Informa, London, https://doi.org/10.1080/09553002.2020.1683636.  

Eaton, J. W. (1994), “UV-mediated cataractogenesis: A radical perspective”, Documenta ophthalmologica, Vol. 88, Springer, London, https://doi.org/10.1007/BF01203677.  

Fatma, N. et al. (2005), “Impaired homeostasis and phenotypic abnormalities in Prdx6-/- mice lens epithelial cells by reactive oxygen species: Increased expression and activation of TGFβ”, Cell death and differentiation, Vol. 12, Nature Portfolio, London, https://doi.org/10.1038/sj.cdd.4401597. 

Fletcher, A. E (2010), “Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration”, Ophthalmic Research, Vol. 44, Karger International, Basel, https://doi.org/10.1159/000316476. 

Ganea, E. and J. J. Harding (2006), “Glutathione-related enzymes and the eye”, Current eye research, Vol. 31/1, Informa, London, https://doi.org/10.1080/02713680500477347. 

Giblin, F. J. et al. (2002), “UVA light in vivo reaches the nucleus of the guinea pig lens and produces deleterious, oxidative effects”, Experimental eye research, Vol. 75/4, Elsevier, Amsterdam, https://doi.org/10.1006/exer.2002.2039. 

Giedzinski, E. et al. (2005), “Efficient production of reactive oxygen species in neural precursor cells after exposure to 250 MeV protons”, Radiation research, Vol. 164/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/rr3369.1. 

Hamada, N. et al. (2014), “Emerging issues in radiogenic cataracts and cardiovascular disease”, Journal of radiation research, Vol. 55/5, Oxford University Press, Oxford, https://doi.org/10.1093/jrr/rru036. 

Hatoum, O. A. et al. (2006), “Radiation induces endothelial dysfunction in murine intestinal arterioles via enhanced production of reactive oxygen species”, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 26/2, Lippincot Williams & Wilkins, Philadelphia, https://doi.org/10.1161/01.ATV.0000198399.40584.8C. 

Hightower, K. and J. McCready (1992), “Mechanisms involved in cataract development following near-ultraviolet radiation of cultured lenses”, Current eye research, Vol. 11/7, Informa, London, https://doi.org/10.3109/02713689209000741. 

Hightower, K. R. (1995), “The role of the lens epithelium in development of UV cataract”, Current eye research, Vol. 14/1, Informa, London, https://doi.org/10.3109/02713689508999916. 

Hua, H. et al. (2019), “Protective effects of lanosterol synthase up-regulation in UV-B-induced oxidative stress”, Frontiers in pharmacology, Vol. 10, Frontiers Media SA, Lausanne,  https://doi.org/10.3389/fphar.2019.00947. 

Huang, L. et al. (2006), “Oxidation-induced changes in human lens epithelial cells 2. Mitochondria and the generation of reactive oxygen species”, Free radical biology & medicine, Vol. 41/6, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2006.05.023.  

Huang, B. et al. (2019), “Amifostine suppresses the side effects of radiation on BMSCs by promoting cell proliferation and reducing ROS production”, Stem Cells International, Vol. 2019, Hindawi, London, https://doi.org/10.1155/2019/8749090. 

Huang, B. et al. (2018), “Sema3a inhibits the differentiation of raw264.7 cells to osteoclasts under 2gy radiation by reducing inflammation”, PLoS ONE, Vol. 13/7, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0200000. 

ICRU (1998), “ICRU report 57: conversion coefficients for use in radiological protection against external radiation”, Journal of the ICRU, Vol. 29/2, SAGE Publishing 

Ismail, A. F. and S. M. El-Sonbaty (2016), “Fermentation enhances Ginkgo biloba protective role on gamma-irradiation induced neuroinflammatory gene expression and stress hormones in rat brain”, Journal of photochemistry and photobiology. B, Biology, Vol. 158, Elsevier, Amsterdam, https://doi.org/10.1016/j.jphotobiol.2016.02.039. 

Ji, Y. et al. (2015), “The mechanism of UVB irradiation induced-apoptosis in cataract”, Molecular and cellular biochemistry, Vol. 401, Springer, London, https://doi.org/10.1007/s11010-014-2294-x. 

Jiang, Q. et al. (2006), “UV radiation down-regulates Dsg-2 via Rac/NADPH oxidase-mediated generation of ROS in human lens epithelial cells”, International Journal of Molecular Medicine, Vol. 18/2, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/ijmm.18.2.381. 

Jurja, S. et al. (2014), “Ocular cells and light: harmony or conflict?”, Romanian Journal of Morphology & Embryology, Vol. 55/2, Romanian Academy Publishing House, Bucharest, pp. 257–261. 

Kang, L. et al. (2020), “Ganoderic acid A protects lens epithelial cells from UVB irradiation and delays lens opacity”, Chinese journal of natural medicines, Vol. 18/12, Elsevier, Amsterdam, https://doi.org/10.1016/S1875-5364(20)60037-1. 

Karam, H. M. and R. R. Radwan (2019), “Metformin modulates cardiac endothelial dysfunction, oxidative stress and inflammation in irradiated rats: A new perspective of an antidiabetic drug”, Clinical and Experimental Pharmacology and Physiology, Vol. 46/12, Wiley-Blackwell, Hoboken, https://doi.org/10.1111/1440-1681.13148. 

Karimi, N. et al. (2017), “Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats”, International Journal of Pharmaceutical Investigation, Vol. 7/3, Phcog Net, Bengaluru, https://doi.org/10.4103/jphi.JPHI_60_17. 

Kłuciński, P. et al. (2008), “Erythrocyte antioxidant parameters in workers occupationally exposed to low levels of ionizing radiation”, Annals of Agricultural and Environmental Medicine, Vol. 15/1, pp. 9-12.   

Kook, S. H. et al. (2015), “Irradiation inhibits the maturation and mineralization of osteoblasts via the activation of Nrf2/HO-1 pathway”, Molecular and Cellular Biochemistry, Vol. 410/1-2, Springer, London, https://doi.org/10.1007/s11010-015-2559-z. 

Kubo, E. et al. (2010), “Protein expression profiling of lens epithelial cells from Prdx6-depleted mice and their vulnerability to UV radiation exposure”, American Journal of Physiology, Vol. 298/2, American Physiological Society, Rockville, https://doi.org/10.1152/ajpcell.00336.2009. 

Lee, J. et al. (2004), “Reactive oxygen species, aging, and antioxidative nutraceuticals”, Comprehensive reviews in food science and food safety, Vol. 3/1, Blackwell Publishing Ltd, Oxford, http://doi.org/10.1111/j.1541-4337.2004.tb00058.x.  

Limoli, C. L. et al. (2007), “Redox changes induced in hippocampal precursor cells by heavy ion irradiation”, Radiation and environmental biophysics, Vol. 46/2, Springer, London, https://doi.org/10.1007/s00411-006-0077-9.  

Limoli, C. L. et al. (2004), “Radiation response of neural precursor cells: linking cellular sensitivity to cell cycle checkpoints, apoptosis and oxidative stress”, Radiation research, Vol. 161/1, Radiation Research Society, Bozeman, https://doi.org/10.1667/rr3112.  

Liu, F. et al. (2019), “Transcriptional response of murine bone marrow cells to total-body carbon-ion irradiation”, Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol. 839, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrgentox.2019.01.014.  

Liu, Y. et al. (2018), “Protective effects of α2macroglobulin on human bone marrow mesenchymal stem cells in radiation injury”, Molecular Medicine Reports, Vol. 18/5, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/mmr.2018.9449.  

Manda, K. et al. (2007), “Melatonin attenuates radiation-induced learning deficit and brain oxidative stress in mice”, Acta neurobiologiae experimentalis, Vol. 67/1, Nencki Institute of Experimental Biology, Warsaw, pp. 63 –70.  

Manda, K., M. Ueno and K. Anzai (2008), “Memory impairment, oxidative damage and apoptosis induced by space radiation: ameliorative potential of alpha-lipoic acid”, Behavioural brain research, Vol. 187/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbr.2007.09.033.  

Mansour, H. H. (2013), “Protective effect of ginseng against gamma-irradiation-induced oxidative stress and endothelial dysfunction in rats”, EXCLI Journal, Vol. 12, Leibniz Research Centre for Working Environment and Human Factors, Dortmund, pp. 766-777. 

Marshall, J. (1985), “Radiation and the ageing eye”, Ophthalmic & physiological optics, Vol. 5, Wiley-Blackwell, Hoboken, https://doi.org.10.1111/j.1475-1313.1985.tb00666.x.  

Padgaonkar, V. A. et al. (2015) “Thioredoxin reductase activity may be more important than GSH level in protecting human lens epithelial cells against UVA light”, Photochemistry and photobiology, Vol. 91/2, Wiley-Blackwell, Hoboken, https://doi.org/10.1111/php.12404.  

Pendergrass, W. et al. (2010), “X-ray induced cataract is preceded by LEC loss, and coincident with accumulation of cortical DNA, and ROS; similarities with age-related cataracts”, Molecular Vision, Vol. 16, Emory University, Atlanta, pp. 1496-513.  

Philipp, J. et al. (2020), “Radiation Response of Human Cardiac Endothelial Cells Reveals a Central Role of the cGAS-STING Pathway in the Development of Inflammation”, Proteomes, Vol. 8/4, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/proteomes8040030.  

Quan, Y. et al. (2021), “Connexin hemichannels regulate redox potential via metabolite exchange and protect lens against cellular oxidative damage”, Redox biology, Vol. 46, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2021.102102.  

Ramadan, R. et al. (2020), “Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage”, Frontiers in Pharmacology, Vol. 11, Frontiers Media SA, Lausanne, https://doi.org/10.3389/fphar.2020.00212 

Rehman, M. U. et al. (2016), “Comparison of free radicals formation induced by cold atmospheric plasma, ultrasound, and ionizing radiation”, Archives of biochemistry and biophysics, Vol. 605, Elsevier, Amsterdam, https://doi.org/10.1016/j.abb.2016.04.005.  

Rogers, C. S. et al. (2004), “The effects of sub-solar levels of UV-A and UV-B on rabbit corneal and lens epithelial cells”, Experimental eye research, Vol. 78, Elsevier, Amsterdam, https://doi.org/10.1016/j.exer.2003.12.011.  

Rong, X. et al. (2019), “TRIM69 inhibits cataractogenesis by negatively regulating p53”, Redox biology, Vol. 22, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2019.101157.  

Rugo, R. E. and R. H. Schiestl (2004), “Increases in oxidative stress in the progeny of X-irradiated cells”, Radiation research, Vol. 162/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/rr3238.  

Santos, A. L., S. Sinha, and A. B. Linder (2018), “The good, the bad, and the ugly of ROS: New insights on aging and aging-related diseases from eukaryotic and prokaryotic model organisms”, Oxidative medicine and cellular longevity, Vol. 2018, Hindawi, London, https://doi.org/10.1155/2018/1941285.  

Schoenfeld, M. P. et al. (2012), “A hypothesis on biological protection from space radiation through the use of new therapeutic gases as medical counter measures”, Medical gas research, Vol. 2/8, BioMed Central Ltd, London, https://doi.org/10.1186/2045-9912-2-8. 

Sharma, U. C. et al. (2018), “Effects of a novel peptide Ac-SDKP in radiation-induced coronary endothelial damage and resting myocardial blood flow”, Cardio-oncology, Vol. 4, BioMed Central Ltd, London,  https://doi.org/10.1186/s40959-018-0034-1.  

Shen, Y. et al. (2018), “Transplantation of bone marrow mesenchymal stem cells prevents radiation-induced artery injury by suppressing oxidative stress and inflammation”, Oxidative Medicine and Cellular Longevity, Vol. 2018, Hindawi, London, https://doi.org/10.1155/2018/5942916.  

Slezak, J. et al. (2017), “Potential markers and metabolic processes involved in the mechanism of radiation-induced heart injury”, Canadian journal of physiology and pharmacology, Vol. 95/10, Canadian Science Publishing, Ottawa, https://doi.org/10.1139/cjpp-2017-0121.   

Soloviev, A. I. and I.V. Kizub (2019), “Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction”, Biochemical pharmacology, Vol. 159, Elsevier, Amsterdam, https://doi.org/10.1016/j.bcp.2018.11.019.  

Soltani, B. (2016), “Nanoformulation of curcumin protects HUVEC endothelial cells against ionizing radiation and suppresses their adhesion to monocytes: potential in prevention of radiation-induced atherosclerosis”, Biotechnology Letters, Vol. 38, Springer, London, https://doi.org/10.1007/s10529-016-2189-x.  

Soucy, K. G. et al. (2011), “HZE 56Fe-Ion Irradiation Induces Endothelial Dysfunction in Rat Aorta: Role of Xanthine Oxidase”, Radiation Research, Vol. 176/4, Radiation Research Society, Bozeman, https://doi.org/10.1667/RR2598.1.  

Soucy, K. G. et al. (2010), “Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta”, Journal of Applied Physiology, Vol. 108/5, American Physiological Society, Rockville, https://doi.org/10.1152/japplphysiol.00946.2009.  

Spector, A. (1990), “Oxidation and aspects of ocular pathology”, The CLAO journal, Vol. 16, Contact Lens Association of Ophthalmologists, Colorado, pp. S8-10.  

Stohs, S. (1995), “The role of free radicals in toxicity and disease”, Journal of Basic and Clinical Physiology and Pharmacology, Vol. 6/3-4, Walter de Gruyter GmbH, Berlin, pp. 205-228.  

Suman, S. et al. (2013), “Therapeutic and space radiation exposure of mouse brain causes impaired DNA repair response and premature senescence by chronic oxidant production”, Aging, Vol. 5/8, Impact Journals, Orchard Park, https://doi.org/10.18632/aging.100587.  

Tahimic, C. G. T., and R. K. Globus (2017), “Redox signaling and its impact on skeletal and vascular responses to spaceflight”, International Journal of Molecular Sciences, Vol. 18/10, Multidisciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms18102153.  

Tangvarasittichai, O. and S. Tangvarasittichai (2018), “Oxidative stress, ocular disease and diabetes retinopathy”, Current pharmaceutical design, Vol. 24/40, Bentham Science Publishers, Sharjah, https://doi.org/10.2174/1381612825666190115121531.  

Taysi, S. et al. (2012), “Zinc administration modulates radiation-induced oxidative injury in lens of rat”, Pharmacognosy Magazine, Vol. 8/2, https://doi.org/10.4103/0973-1296.103646 

Tian, Y. et al. (2017), “The Impact of Oxidative Stress on the Bone System in Response to the Space Special Environment”, International Journal of Molecular Sciences, Vol. 18/10, Multidisciplinary Digital Publishing Institute, Basel,  https://doi.org/10.3390/ijms18102132.  

Tseng, B. P. et al. (2014), “Functional consequences of radiation-induced oxidative stress in cultured neural stem cells and the brain exposed to charged particle irradiation”, Antioxidants & redox signaling, Vol. 20/9, Mary Ann Leibert Inc., Larchmont, https://doi.org/10.1089/ars.2012.5134.  

Turner, N. D. et al. (2002), “Opportunities for nutritional amelioration of radiation-induced cellular damage”, Nutrition, Vol. 18/10, Elsevier Inc, New York, http://doi.org/10.1016/S0899-9007(02)00945-0.  

Ungvari, Z. et al. (2013), “Ionizing Radiation Promotes the Acquisition of a Senescence-Associated Secretory Phenotype and Impairs Angiogenic Capacity in Cerebromicrovascular Endothelial Cells: Role of Increased DNA Damage and Decreased DNA Repair Capacity in Microvascular Radiosensitivity”, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 68/12, Oxford University Press, Oxford, https://doi.org/10.1093/gerona/glt057.  

Varma, S. D. et al. (2011), “Role of ultraviolet irradiation and oxidative stress in cataract formation-medical prevention by nutritional antioxidants and metabolic agonists”, Eye & contact lens, Vol. 37/4, Lippincot Williams & Wilkins, Philadelphia, https://doi.org/10.1097/ICL.0b013e31821ec4f2.  

Venkatesulu, B. P. et al. (2018), “Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms”, JACC: Basic to Translational Science, Vol. 3/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.jacbts.2018.01.014.  

Veeraraghavan, J. et al. (2011), “Low-dose gamma-radiation-induced oxidative stress response in mouse brain and gut: regulation by NFκB-MnSOD cross-signaling”, Mutation research, Vol. 718/1-2, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrgentox.2010.10.006.  

Wang, C. et al. (2016), “Protective effects of cerium oxide nanoparticles on MC3T3-E1 osteoblastic cells exposed to X-ray irradiation”, Cellular Physiology and Biochemistry, Vol. 38/4, Karger International, Basel, https://doi.org/10.1159/000443092.  

Wang, H. et al. (2019a), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, https://doi.org/10.7150/ijbs.35460.  

Wang, H. et al. (2019b), “Gamma Radiation-Induced Disruption of Cellular Junctions in HUVECs Is Mediated through Affecting MAPK/NF-κB Inflammatory Pathways”, Oxidative Medicine and Cellular Longevity, Vol. 2019, Hindawi, London, https://doi.org/10.1155/2019/1486232.  

Wegener, A. R. (1994), “In vivo studies on the effect of UV-radiation on the eye lens in animals”, Documenta ophthalmologica, Vol. 88, Springer, London, https://doi.org/10.1007/BF01203676.  

Weinreb O. and A. Dovrat (1996), “Transglutaminase involvement in UV-A damage to the eye lens”, Experimental eye research, Vol. 63/5, Elsevier, London, https://doi.org/10.1006/exer.1996.0150.  

Yang, H. et al. (2020), “Cytoprotective role of humanin in lens epithelial cell oxidative stress-induced injury”, Molecular medicine reports, Vol. 22/2, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/mmr.2020.11202.  

Yao, K. et al. (2008), “The flavonoid, fisetin, inhibits UV radiation-induced oxidative stress and the activation of NF-κB and MAPK signaling in human lens epithelial cells”, Molecular Vision, Vol. 14, Emory University, Atlanta, pp. 1865-1871.  

Yao, J. et al. (2009), “UVB radiation induces human lens epithelial cell migration via NADPH oxidase-mediated generation of reactive oxygen species and up-regulation of matrix metalloproteinases”, International Journal of Molecular Medicine, Vol. 24/2, Spandidos Publishing Ltd, Athens, https://doi.org/10.3892/ijmm_00000218.  

Yves, C. (2000), "Oxidative stress and Alzheimer disease", The American Journal of Clinical Nutrition, Vol. 71/2, https://doi.org/10.1093/ajcn/71.2.621s. 

Zhang, J. et al. (2012), “Ultraviolet radiation-induced cataract in mice: The effect of age and the potential biochemical mechanism”, Investigative ophthalmology & visual science, Vol. 53, Association for Research in Vision and Ophthalmology, Rockville, https://doi.org/10.1167/iovs.12-10482.  

Zhang, L. et al. (2020), “Amifostine inhibited the differentiation of RAW264.7 cells into osteoclasts by reducing the production of ROS under 2 Gy radiation”, Journal of Cellular Biochemistry, Vol. 121/1, John Wiley & Sons, Ltd., Hoboken, https://doi.org/10.1002/jcb.29247.  

Zhang, L. et al. (2018), “Astragalus polysaccharide inhibits ionizing radiation-induced bystander effects by regulating MAPK/NF-κB signaling pathway in bone mesenchymal stem cells (BMSCs)”, Medical Science Monitor, Vol. 24, International Scientific Information, Inc., Melville, https://doi.org/10.12659/MSM.909153.  

Zigman, S. et al. (2000), “Effects of intermittent UVA exposure on cultured lens epithelial cells”, Current Eye Research, Vol. 20/2, Informa UK Limited, London, https://doi.org/10.1076/0271-3683(200002)2021-DFT095.  

Zigman, S. et al. (1995), “Damage to cultured lens epithelial cells of squirrels and rabbits by UV-A (99.9%) plus UV-B (0.1%) radiation and alpha tocopherol protection”, Molecular and cellular biochemistry, Vol. 143, Springer, London, https://doi.org/10.1007/BF00925924.  

Relationship: 2832: Energy Deposition leads to Tissue resident cell activation

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

The domain of applicability is related to any vertebrates and invertebrates with an innate immune system regardless of sex (Beck & Habicht, 1996, Sonetti et al., 1994, Rowley, 1996). The deposition of energy is most detrimental in utero because tissue resident cells and their pro-inflammatory responses can cause permanent tissue damage  (Heiervang et al., 2010, McCollough et al., 2007, Kannan et al., 2007). 

Key Event Relationship Description

Deposition of energy refers to particles that have sufficient energy to penetrate biological tissue leading to ionization events that can break water molecules and form free radicals. These can damage sensitive macromolecules such as DNA, protein and lipids (Chen, Oyarzabal & Hong, 2016; Mavragani et al., 2016). Ionization events occur from many types of radiation including, X-rays, gamma-rays, alpha particles, beta particles, heavy ions, and neutrons. X-rays and gamma rays induce sparse ionization events and energy is exponentially absorbed by tissues. Conversely, energetic charged particles can cause dense ionization events, leading to clustered damage and secondary ionization events (Niemantsverdriet et al., 2012). 

When sufficient energy is deposited it can damage the cellular environment; this releases danger signals either passively when the ionization events induce cell death, or actively by cells undergoing life threatening stress (Denning et al., 2019; Vénéreau, Ceriotti & Bianchi, 2015). These signaling molecules, such as alarmins or damage-associated molecular pattern molecules (DAMPs),  promote an inflammatory and regenerative environment by activating tissue resident cells (Chen, Oyarzabal & Hong, 2016; Vénéreau, Ceriotti & Bianchi, 2015). Resident immune cells, such as macrophages and dendritic cells, use pattern recognition receptors on their surfaces to detect alarmins and DAMPs which initiate their activation and proliferation (Chen, Oyarzabal & Hong, 2016; Mavragani et al., 2016). Activated cells can then regulate the recruitment of circulating immune cells and initiate inflammation to remove damaged cells, eliminate harmful stimuli, and promote tissue repair (Schaue et al., 2015; Roh & Sohn, 2018).  However, uncontrolled inflammation can then lead to a state of disease progression. 

Evidence Supporting this KER

Overall Weight of Evidence: Moderate 

There is strong biological evidence and mechanistic understanding linking deposition of energy to tissue resident activation. It is widely accepted that deposition of energy can cause the activation of resident tissue cells (Di Maggio et al., 2015; Frey et al., 2015; Mavragani et al., 2016; Multhoff & Radons, 2012; Pinto et al., 2016; Rodel et al., 2012; Schaue et al., 2015; Yahyapour et al., 2018; Zhao & Robbins, 2009; Rienecker et al., 2021). Ionization of local tissue leads to direct tissue damage, reduced cellular homeostasis, genotoxic stress, and oxidative stress (Mavragani et al., 2016; Yahyapour et al., 2018). This damage can initiate tissue resident cell activation (Davies et al., 2013; Langston, Shibata & Horng, 2017; Rienecker et al., 2021). Primary damage and follow-on free-radical events typically occur within microseconds, but the inflammatory response carries on the damage through waves of reactive oxygen species generation as well as cytokine and chemokine release (Schaue et al., 2015). The resultant loss of cellular homeostasis, as well as primary and secondary cellular damage leads to the release of DAMPs (Mavragani et al., 2016; Yahyapour et al., 2018). Resident cells then use pattern recognition receptors to detect DAMPs resulting in their activation through a series of intracellular signaling cascades (Mavragani et al., 2016; Yahyapour et al., 2018). 

There are many resident cells that become activated in response to radiation damage including lymphocytes, neutrophils, endothelial cells, and dendritic cells. Among the resident cells, macrophages are present in virtually all tissues and are the first line of defense against foreign pathogens and stressors. Resident macrophages have a ramified morphology with long, dynamic processes and are constantly surveying for signals of injury or infection (Betlazar et al., 2016; Paladini et al., 2021). They are also scavenger cells which engulf metabolites and debris from surrounding apoptotic cells to maintain healthy organs and tissues. When damage is detected, local macrophages become activated and move to the site of injury, where they signal other immune cells and release cytokines, chemokines, and other soluble molecules to mediate wound healing and initiate an inflammatory response (Hladik & Tapio, 2016; Paladini et al., 2021; Yahyapour et al., 2016; Rienecker et al., 2021). Resident macrophages detect endogenous cellular components released from damaged, stressed, or dying cells through pattern recognition receptors such as toll-like receptors (TLRs) (Chen, Oyarzabal & Hong, 2016; Yahyapour et al., 2016). TLRs can detect a wide variety of DAMPs including those potentially formed by deposition of energy ( i.e., oxidized DNA, uric acid, ATP and high-mobility group box 1 protein) (Yahyapour et al., 2016). When TLRs detect DAMPs in the extracellular environment, they initiate intracellular signaling cascades that lead to the nuclear translocation of transcription factors, such as nuclear factor-κB (NF-κB), to induce the production of proinflammatory cytokines and chemokines (Chen, Oyarzabal & Hong, 2016; Yahyapour et al., 2018). The resident macrophages also initiate granulocyte-macrophage colony formation and recruitment of early myeloid progenitors to the site of injury (Schaue et al., 2015). 

This response has been shown to occur across organs and tissue types using the same underlying mechanisms (Chen, Oyarzabal & Hong, 2016, Mavragani et al., 2016, Schaue et al., 2015). However, tissues are distinct in the types of activated cells and the resulting inflammatory responses. For example, the liver hosts the largest population of macrophages (Kupper cells) and is enriched with T lymphocytes or natural killer cells (Szabo, Mandrekar & Dolganiuc, 2007). Local Kupper cells use pattern recognition receptors to detect local radiation damage which leads to their activation (Szabo, Mandrekar & Dolganiuc, 2007). Activated cells secrete proinflammatory mediators, recruit macrophages and regulate the response of local T lymphocytes (Szabo, Mandrekar & Dolganiuc, 2007). In the lungs, radiation damage is first detected by local epithelial cells that produce pro-inflammatory mediators including cytokines and reactive oxygen species (Chen et al., 2018). These mediators stimulate mucus secretion by goblet cells and recruit macrophages and dendritic cells to initiate inflammation (Moldoveanu et al., 2009). In some organs, such as the brain, resident immune cells are abundant because the organ is separated from the immune system by the blood brain barrier to protect it from infection by foreign cells (Banks & Erickson, 2010). It has been shown that brain exposure to ionizing radiation can initiate activation of other types of resident immune cells, such as microglia and astrocytes (Betlazar et al., 2016). Microglial cells are the first line of defense in response to radiation damage and become activated in response to DAMPs released from local damaged cells (Betlazar et al., 2016). Microglia cells release pro-inflammatory mediators to regulate an inflammatory response and recruit additional immune cells to the site of injury (Betlazar et al., 2016). Microglia can subsequently induce astrocyte activation via the COX-2 pathway in the presence of a stressor (Betlazar et al., 2016; Cucinotta et al., 2014; Paladini et al., 2021). When damage is detected, astrocytes proliferate and form scar tissue via reactive gliosis (Makale et al., 2017). 

The empirical evidence surrounding this KER comes from research using in vitro and in vivo models. All organ systems are  vulnerable to tissue resident activation from deposition of energy, however, provided below are consistent example of  evidence from brain studies. Tissue resident cell activation is typically determined in the brain through the observation of the activation or proliferation of brain-resident immune cells, microglia and astrocytes.  

 The data consistently shows that direct deposition of energy can elicit damage to tissues and induce resident immune cell activation. The literature space is populated with studies examining effects of high doses (>2 Gy) of radiation with sparse studies examining effects for lower dose exposures (<1 Gy). Much of the high dose evidence is from work exposing rodent models to doses between 0 and 200 cGy of heavy ions and/or protons via whole body irradiation (Allen et al., 2020; Krukowski et al., 2018a; Parihar et al., 2020; Parihar et al., 2018; Parihar et al., 2016; Poulose et al., 2011; Raber et al., 2019; Sumam et al., 2013). Some studies exposing rodents to high energy particles use high dose ranges (up to 4 Gy) (Cummings et al., 2007; Rola et al., 2008). Also included are studies using high doses (1-10 Gy) of X-rays or gamma rays used in a clinical setting (Acharya et al., 2016; Casciati et al., 2016; Chen et al., 2016; Hua et al., 2012; Hwang et al., 2006; Mizumatsu et al., 2003; Monje et al., 2002; Rola et al., 2007; Rola et al., 2004). In addition, very high-dose studies, using doses up to 25-45 Gy were included which showed consistent tissue resident activation following deposition of energy (Chiang, McBride & Withers, 1993; Dey et al., 2020; Kyrkanides et al., 1999; Moravan et al., 2011). 

Dose Concordance  

The literature supports the dose-concordance of the relationship between energy deposition and tissue resident cell activation, specifically glial cells, following exposure to ionizing radiation. Some  studies, using exposures involving  16O, 48Ti, 4He and protons, observed significant increases in activation at doses  of 5, 15, 30 or 50 cGy (Allen et al., 2020; Krukowski et al., 2018a; Parihar et al., 2016; Parihar et al., 2018; Parihar et al., 2020). These studies report an approximate 1.25- to 5-fold increase in microglia markers post-irradiation. Astrocyte activation was not reported in these studies. Other lower dose studies observed a radiation dose-dependent 1.3- to 14-fold increase in markers indicating activation of astrocytes and/or microglia (Casiati et al., 2016; Cummings et al., 2007; Poulose et al., 2011; Raber et al., 2019; Rola et al., 2008; Suman et al., 2013). These studies used 56Fe, protons, 16O or 28 Si, gamma rays and X-rays at doses ranging from 1-4 Gy. Various stressors at moderate doses further support the dose concordance of energy deposition and activation of tissue resident cells (Acharya et al., 2016; Dey et al., 2020; Hua et al., 2012; Monje et al., 2002; Rola et al., 2007; Rola et al., 2004). Consistency in the dose-response relationship was mostly exhibited at the higher doses (2-10 Gy), with reports showing a steady dose-dependent increase in resident tissue activation (Chen et al., 2016; Casciati et al., 2016; Hwang et al., 2006; Rola et al., 2008). With very high doses of radiation (up to 45 Gy), significant increases of GFAP and Mac-I levels in glia are observed (Chiang, McBride & Withers, 1993; Kyrkanides et al., 1999; Mizumatsu et al., 2003; Moravan et al., 2011). Additionally, increase in CD68+ cells  have been shown following a total dose of 26 Gy (Dey et al., 2020). Further studies using mouse primary microglial cultures irradiated with X-rays at 10 Gy have shown a 2.5-fold increase in tissue resident cell activation.  In vivo mice irradiated with 30 Gy also show a 9-fold increase in microglial activation (Xu et al., 2015). In general, these studies highlight that with an increase in deposited energy larger amounts of primary and secondary tissue damage occurs, which leads to increased proliferation and activation of resident immune cells. 

Time Concordance  

Many long-term and a few short-term studies find tissue-resident cell activation after deposition of energy. Mice irradiated with 35 Gy of gamma rays show activated astrocytes and microglia 4 h after irradiation (Kyrkanides et al., 1999). Rats irradiated with X-rays at 15 Gy show activation of astrocytes at 6 h (Hwang et al., 2006). Many studies show 1.2- to 3-fold increased activation one or a few days after irradiation in rats and mice (Casciati et al., 2016; Hwang et al., 2006; Kyrkanides et al., 1999; Moravan et al., 2011; Poulose et al., 2011). Furthermore, it has also been shown that activation continues until 1 year, measured after weeks and months, with a maximum 14-fold increase in marker levels shown after 2 months post-irradiation (Acharya et al., 2016; Allen et al., 2020; Casciati et al., 2016; Chiang, McBride & Withers, 1993; Chen et al., 2016; Cummings et al., 2007; Dey et al., 2020; Hua et al., 2012; Kyrkanides et al., 1999; Mizumatsu et al., 2003; Monje et al., 2002; Moravan et al., 2011; Parihar et al., 2020; Parihar et al., 2018; Parihar et al., 2016; Poulose et al., 2011; Raber et al., 2019; Rola et al., 2008; Rola et al., 2004; Suman et al., 2013). 

Incidence Concordance 

No available data. 

Essentiality 

Since deposition of energy is a physical stressor, it can be shielded, but chemicals cannot effectively block or decrease it. Thus further research is required to determine the effect of shielding radiation on the activation of tissue resident cells. Since deposited energy initiates events immediately, the removal of deposited energy, a physical stressor, also supports the  essentiality of the key event. Studies that do not deposit energy are observed to have no downstream effects.  

• There is no consensus about sex-related responses to radiation exposure and the resulting activation of tissue resident cells. Krukowski et al. (2018a) and Parihar et al. (2020) found that female mice were immune to the effects of 0.3 and 0.5 Gy radiation on cell activation, while Raber et al. (2019) found that only female mice showed increased activated cells after 2 Gy. 

• A large amount of uncertainty surrounds the impact of low-dose ionizing radiation on tissue resident cell activation. More evidence is required to determine the relationship between ionizing radiation at doses < 1 Gy and tissue-resident cell activation. 

Quantitative Understanding of the Linkage

Dose Concordance  

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated. 

Time Concordance  

N/A

References

Acharya, M. M. et al. (2016), "Elimination of microglia improves cognitive function following cranial irradiation", Scientific Reports, Vol. 6/1, Nature Publishing Group, https://doi.org/10.1038/srep31545. 

Allen, B. D. et al. (2020), "Mitigation of helium irradiation-induced brain injury by microglia depletion", Journal of Neuroinflammation, Vol. 17/1, Nature, https://doi.org/10.1186/s12974-020-01790-9. 

Al Zaman, M. A. and Q. M. R. Nizam. (2022), "Study on Shielding Effectiveness of a Combined Radiation Shield for Manned Long Termed Interplanetary Expeditions", Journal of Space Safety Engineering, Vol. 9/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.jsse.2021.12.003. 

Banks, W. A. and M. A. Erickson. (2010), "The blood–brain barrier and immune function and dysfunction", Neurobiology of Disease, Vol. 37/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.nbd.2009.07.031. 

Beck, G. and G. S. Habicht. (1996), "Immunity and the Invertebrates", Scientific American, Vol. 275/5, Nature, https://doi.org/10.1038/scientificamerican1196-60. 

Betlazar, C. et al. (2016), "The impact of high and low dose ionising radiation on the central nervous system", Redox Biology, Vol. 9, Elsevier, Amsterdam, https://doi.org/10.1016/j.redox.2016.08.002. 

Capri, M. et al. (2019), "Recovery from 6‐month spaceflight at the International Space Station: muscle‐related stress into a proinflammatory setting", The FASEB Journal, Vol. 33/4, Wiley, https://doi.org/10.1096/fj.201801625R. 

Casciati, A. et al. (2016), "Age-related effects of X-ray irradiation on mouse hippocampus", Oncotarget, Vol. 7/19, https://doi.org/10.18632/oncotarget.8575. 

Chen, H. et al. (2016), "Delayed activation of human microglial cells by high dose ionizing radiation", Brain Research, Vol. 1646, Elsevier, Amsterdam, https://doi.org/10.1016/j.brainres.2016.06.002. 

Chen, L. et al. (2018), "Inflammatory responses and inflammation-associated diseases in organs", Oncotarget, Vol. 9/6, https://doi.org/10.18632/oncotarget.23208. 

Chen, S.-H., E. A. Oyarzabal and J.-S. Hong. (2016), "Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration", Current Opinion in Pharmacology, Vol. 26, Elsevier, Amsterdam, https://doi.org/10.1016/j.coph.2015.10.001. 

Chiang, C. S., W. H. McBride and H. R. Withers. (1993), "Radiation-induced astrocytic and microglial responses in mouse brain", Radiotherapy and Oncology, Vol. 29/1, Elsevier, Amsterdam, https://doi.org/10.1016/0167-8140(93)90174-7. 

Cucinotta, F. A. et al. (2014), "Space radiation risks to the central nervous system", Life Sciences in Space Research, Vol. 2, Elsevier, Amsterdam, https://doi.org/10.1016/j.lssr.2014.06.003. 

Cummings, P. et al. (2007), "High-energy (hze) radiation exposure causes delayed axonal degeneration and astrogliosis in the central nervous system of rats", Gravitational and Space Research, Vol. 20/2. 

Davies, L. C. et al. (2013), "Tissue-resident macrophages", Nature Immunology, Vol. 14/10, Nature, https://doi.org/10.1038/ni.2705. 

Denning, N.-L. et al. (2019), "DAMPs and NETs in Sepsis", Frontiers in Immunology, Vol. 10, Frontiers, https://doi.org/10.3389/fimmu.2019.02536. 

Dey, D. et al. (2020), "Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy", Radiation Research, Vol. 193/5, BioOne, https://doi.org/10.1667/RR15540.1. 

Di Maggio, F. M. et al. (2015), "Portrait of inflammatory response to ionizing radiation treatment", Journal of Inflammation, Vol. 12/1, Nature, https://doi.org/10.1186/s12950-015-0058-3. 

Frey, B. et al. (2015), "Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases", Cancer Letters, Vol. 368/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.canlet.2015.04.010. 

Heiervang, K. S. et al. (2010), "Effect of low dose ionizing radiation exposure in utero on cognitive function in adolescence", Scandinavian Journal of Psychology, Vol. 51/3, Wiley, https://doi.org/10.1111/j.1467-9450.2010.00814.x. 

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research - Reviews in Mutation Research, Vol. 770, Elsevier, Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.003. 

Hua, K. et al. (2012), "Regionally Distinct Responses of Microglia and Glial Progenitor Cells to Whole Brain Irradiation in Adult and Aging Rats", PLoS ONE, Vol. 7/12, PLOS, San Francisco, https://doi.org/10.1371/journal.pone.0052728. 

Hwang, S. Y. et al. (2006), "Ionizing radiation induces astrocyte gliosis through microglia activation", Neurobiology of Disease, Vol. 21/3, Academic Press, https://doi.org/10.1016/j.nbd.2005.08.006. 

Kannan, S. et al. (2007), "Microglial Activation in Perinatal Rabbit Brain Induced by Intrauterine Inflammation: Detection with 11C-(R)-PK11195 and Small-Animal PET", Journal of Nuclear Medicine, Vol. 48/6, https://doi.org/10.2967/jnumed.106.038539. 

Krukowski, K. et al. (2018a), "Female mice are protected from space radiation-induced maladaptive responses", Brain, Behavior, and Immunity, Vol. 74, Academic Press Inc., https://doi.org/10.1016/j.bbi.2018.08.008. 

Krukowski, K. et al. (2018b), "Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits", Scientific Reports 2018 8:1, Vol. 8/1, Nature Publishing Group, https://doi.org/10.1038/s41598-018-26039-7. 

Kyrkanides, S. et al. (1999), "TNFα and IL-1β mediate intercellular adhesion molecule-1 induction via microglia-astrocyte interaction in CNS radiation injury", Journal of Neuroimmunology, Vol. 95/1–2, Elsevier, Amsterdam, https://doi.org/10.1016/S0165-5728(98)00270-7. 

Langston, P. K., M. Shibata and T. Horng. (2017), "Metabolism Supports Macrophage Activation", Frontiers in Immunology, Vol. 8, Frontiers, https://doi.org/10.3389/fimmu.2017.00061. 

Makale, M. T. et al. (2017), "Mechanisms of radiotherapy-associated cognitive disability in patients with brain tumours", Nature Reviews Neurology, Vol. 13/1, Nature, https://doi.org/10.1038/nrneurol.2016.185. 

Mavragani, I. V. et al. (2016), "Key mechanisms involved in ionizing radiation-induced systemic effects. A current review", Toxicology Research, Vol. 5/1, Oxford University Press, Oxford, https://doi.org/10.1039/c5tx00222b. 

McCollough, C. H. et al. (2007), "Radiation Exposure and Pregnancy: When Should We Be Concerned?", RadioGraphics, Vol. 27/4, Radiological Society of North America, Oak Brook, https://doi.org/10.1148/rg.274065149. 

Mizumatsu, S. et al. (2003), "Extreme sensitivity of adult neurogenesis to low doses of X-irradiation", Cancer Research, Vol. 63/14. 

Moldoveanu, B. et al. (2009), "Inflammatory mechanisms in the lung.", Journal of inflammation research, Vol. 2, pp. 4021–4027, American Association for Cancer Research. 

Monje, M. L. et al. (2002), "Irradiation induces neural precursor-cell dysfunction", Nature Medicine, Vol. 8/9, Nature, https://doi.org/10.1038/nm749. 

Moravan, M. J. et al. (2011), "Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain", Radiation Research, Vol. 176/4, BioOne, https://doi.org/10.1667/RR2587.1. 

Multhoff, G. and J. Radons. (2012), "Radiation, Inflammation, and Immune Responses in Cancer", Frontiers in Oncology, Vol. 2, Frontiers, https://doi.org/10.3389/fonc.2012.00058. 

Niemantsverdriet, M. et al. (2012), "High and Low LET Radiation Differentially Induce Normal Tissue Damage Signals", International Journal of Radiation Oncology*Biology*Physics, Vol. 83/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.ijrobp.2011.09.057. 

Paladini, M. S. et al. (2021), "Microglia depletion and cognitive functions after brain injury: From trauma to galactic cosmic ray", Neuroscience Letters, Vol. 741, Elsevier, Amsterdam, https://doi.org/10.1016/j.neulet.2020.135462. 

Parihar, V. K. et al. (2016), "Cosmic radiation exposure and persistent cognitive dysfunction", Scientific Reports, Vol. 6/June, Nature Publishing Group, https://doi.org/10.1038/srep34774. 

Parihar, V. K. et al. (2018), "Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice", Experimental Neurology, Vol. 305, Academic Press Inc., https://doi.org/10.1016/j.expneurol.2018.03.009. 

Parihar, V. K. et al. (2020), "Sex-Specific Cognitive Deficits Following Space Radiation Exposure", Frontiers in behavioral neuroscience, Vol. 14, Frontiers, https://doi.org/10.3389/fnbeh.2020.535885. 

Patel, R. et al. (2020), "Protons and High-Linear Energy Transfer Radiation Induce Genetically Similar Lymphomas With High Penetrance in a Mouse Model of the Aging Human Hematopoietic System.", International journal of radiation oncology*biology*physics, Vol. 108/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.ijrobp.2020.06.070. 

Pinto, A. et al. (2016), "Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities", Scientific Reports, Vol. 6/1, Nature, https://doi.org/10.1038/srep18765. 

Poulose, S. M. et al. (2011), "Exposure to 16O-particle radiation causes aging-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy", Radiation Research, Vol. 176/6, BioOne, https://doi.org/10.1667/RR2605.1. 

Raber, J. et al. (2019), "Combined Effects of Three High-Energy Charged Particle Beams Important for Space Flight on Brain, Behavioral and Cognitive Endpoints in B6D2F1 Female and Male Mice", Frontiers in physiology, Vol. 10, Frontiers, https://doi.org/10.3389/fphys.2019.00179. 

Rienecker, K. D. A. et al. (2021), "Microglia: Ally and Enemy in Deep Space", Neuroscience & Biobehavioral Reviews, Vol. 126, https://doi.org/10.1016/j.neubiorev.2021.03.036. 

Rodel, F. et al. (2012), "Modulation of Inflammatory Immune Reactions by Low-Dose Ionizing Radiation: Molecular Mechanisms and Clinical Application", Current Medicinal Chemistry, Vol. 19/12, Bentham Science Publishers, https://doi.org/10.2174/092986712800099866. 

Roh, J. S. and D. H. Sohn. (2018), "Damage-Associated Molecular Patterns in Inflammatory Diseases.", Immune network, Vol. 18/4, https://doi.org/10.4110/in.2018.18.e27. 

Rola, R. et al. (2008), "Hippocampal Neurogenesis and Neuroinflammation after Cranial Irradiation with 56 Fe Particles", Radiation Research, Vol. 169/6, BioOne, https://doi.org/10.1667/RR1263.1. 

Rola, R. et al. (2004), "Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice", Experimental Neurology, Vol. 188/2, Elsevier, Amsterdam, https://doi.org/10.1016/j.expneurol.2004.05.005. 

Rola, R. et al. (2007), "Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis", Free radical biology & medicine, Vol. 42/8, Elsevier, Amsterdam, https://doi.org/10.1016/j.freeradbiomed.2007.01.020. 

Rowley, A. F. (1996), "The evolution of inflammatory mediators", Mediators of inflammation, Vol. 5/1, Hindawi, https://doi.org/10.1155/S0962935196000014. 

Schaue, D. et al. (2015), "Radiation and inflammation", Seminars in radiation oncology, Vol. 25/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.semradonc.2014.07.007. 

Sonetti, D. et al. (1994), "Microglia in invertebrate ganglia", Proceedings of the National Academy of Sciences of the United States of America, Vol. 91/19, National Academy of Science, https://doi.org/10.1073/pnas.91.19.9180. 

Suman, S. et al. (2013), "Therapeutic and space radiation exposure of mouse brain causes impaired dna repair response and premature senescence by chronic oxidant production", Aging, Vol. 5/8, https://doi.org/10.18632/aging.100587. 

Szabo, G., P. Mandrekar and A. Dolganiuc. (2007), "Innate immune response and hepatic inflammation", Seminars in liver disease, Vol. 27/4, Thieme, https://doi.org/10.1055/s-2007-991511. 

Vénéreau, E., C. Ceriotti and M. E. Bianchi. (2015), "DAMPs from Cell Death to New Life", Frontiers in immunology, Vol. 6, Frontiers, https://doi.org/10.3389/fimmu.2015.00422. 

Xu, P. et al. (2015), "Extracellular ATP enhances radiation-induced brain injury through microglial activation and paracrine signaling via P2X7 receptor", Brain, Behavior, and Immunity, Vol. 50, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbi.2015.06.020. 

Yahyapour, R. et al. (2018), "Radiation-induced inflammation and autoimmune diseases", Military Medical Research, Vol. 5/1, Nature, https://doi.org/10.1186/s40779-018-0156-7. 

Zhao, W. and M. Robbins. (2009), "Inflammation and Chronic Oxidative Stress in Radiation-Induced Late Normal Tissue Injury: Therapeutic Implications", Current Medicinal Chemistry, Vol. 16/2, Bentham Science, https://doi.org/10.2174/092986709787002790. 

Relationship: 3316: Oxidative Stress leads to Altered Stress Response Signaling

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Based on the prioritized studies presented here, the evidence of taxonomic applicability is low for humans despite there being strong plausibility as the evidence only includes in vitro human cell-derived models. The taxonomic applicability for mice and rats is considered high as there is much available data using in vivo rodent models that demonstrate the concordance of the relationship. The taxonomic applicability was determined to be moderate for pigs as only one in vivo study provided meaningful support to the relationship. In terms of sex applicability, all in vivo studies that indicated the sex of the animals used male animals, therefore, the evidence for males is high and females is considered to be low for this KER. The majority of studies used adolescent animals, with a few using adult animals. Preadolescent animals were not used to support the KER; however, the relationship in preadolescent animals is still plausible. 

Key Event Relationship Description

Oxidative stress occurs when the production of free radicals exceeds the capacity of cellular antioxidant defenses (Cabrera & Chihuailaf, 2011). Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are both free radicals that can contribute to oxidative stress (Ping et al., 2020); however, ROS are more commonly studied than RNS (Nagane et al., 2021). ROS can mediate oxidative damage to biomacromolecules as they react with DNA, proteins and lipids, resulting in functional changes to these molecules (Ping et al., 2020). For example, ROS acting on lipids creates lipid peroxidation (Cabrera & Chihuailaf, 2011). 

Many signaling pathways control and maintain physiological balance within a living organism, and these can be impacted by oxidative stress. Excessive reactive oxygen and nitrogen species (RONS) during oxidative stress can modify biological molecules and directly cause DNA damage, which can lead to altered signal transduction pathways (Hughson, Helm & Durante, 2018; Lehtinen & Bonni, 2006; Nagane et al., 2021; Ping et al., 2020; Ramadan et al., 2021; Schmidt-Ullrich et al., 2000; Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016; Venkatesulu et al., 2018; Zhang et al., 2016). Different cell types can express distinct cellular pathways that can have varied response to an increase in oxidative stress. For example, oxidative stress in endothelial cells has been shown to inhibit the insulin-like growth factor 1 receptor (IGF-1R) and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway and to activate the mitogen-activated protein kinase (MAPK) pathway, which can then have downstream detrimental effects (Ping et al., 2020). The MAPK family pathway is also activated in the central nervous system (CNS) in response to oxidative stress through calcium-induced phosphorylation of several kinases. These include phosphoinositide 3-kinase (PI3K), protein kinase A (PKA) and protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII) (Lehtinen & Bonni, 2006; Li et al., 2013; Ramalingam & Kim, 2012).

Evidence Supporting this KER

Overall weight of evidence: High 

Many reviews describe the role of oxidative stress in altered signaling. The mechanisms through which oxidative stress can contribute to changes in various signaling pathways are well-described. For example, oxidative stress can directly alter signaling pathways through protein oxidation (Ping et al., 2020; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). Oxidation of cysteine and methionine residues, which are particularly sensitive to oxidation, can cause conformational change, protein expansion, and degradation, leading to changes in the protein levels of signaling pathways (Ping et al., 2020). Furthermore, oxidation of key residues in signaling proteins can alter their function, resulting in altered signaling. For example, oxidation of methionine 281 and 282 in the Ca2+/calmodulin binding domain of Ca2+/calmodulin-dependent protein kinase II (CaMKII) leads to constitutive activation of its kinase activity and subsequent downstream alterations in signaling pathways (Li et al., 2013; Ping et al., 2020). Similarly, during oxidative stress, tyrosine phosphatases can be inhibited by oxidation of a catalytic cysteine residue, resulting in increased phosphorylation of proteins in various signaling pathways (Schmidt-Ullrich et al., 2000; Valerie et al., 2007). Particularly relevant to this are the MAPK pathways. For example, the extracellular signal-regulated kinase (ERK) pathway is activated by upstream tyrosine kinases and relies on tyrosine phosphatases for deactivation (Lehtinen & Bonni, 2006; Valerie et al., 2007). 

Furthermore, oxidative stress can indirectly influence signaling pathways through oxidative DNA damage which can lead to mutations or changes in the gene expression of proteins in signaling pathways (Ping et al., 2020; Schmidt-Ullrich et al., 2000; Valerie et al., 2007). DNA damage surveillance proteins like ataxia telangiectasia mutated (ATM) kinase and ATM/Rad3-related (ATR) protein kinase phosphorylate over 700 proteins, leading to changes in downstream signaling (Nagane et al., 2021; Schmidt- Ullrich et al., 2000; Valerie et al., 2007). For example, ATM, activated by oxidative DNA damage, phosphorylates many proteins in the ERK, p38, and Jun N-terminal kinase (JNK) MAPK pathways, leading to various downstream effects (Nagane et al., 2021; Schmidt-Ullrich et al., 2000). 

The response of oxidative stress on signaling pathways has been studied extensively in various diseases. Herein presented are examples relevant to a few cell types related to impaired learning and memory.. Many other pathways are plausible but available research has highlighted these to be critical to disease. 

Endothelial cells: Endothelial cells can normally produce ROS. Antioxidant enzymes and the glutathione redox buffer control the redox state of vascular tissues. However, the dysregulation of signaling pathways can occur in the endothelium when oxidative stress is favored (Soloviev & Kizub, 2019). Oxidative stress can activate the acidic sphingomyelinase (ASMase)/ceramide pathway, the MAPK pathways, the p53/p21 pathway, and the signaling proteins p16 and p21, as well as inhibit the PI3K/Akt pathway (Hughson, Helm & Durante, 2018; Nagane et al., 2021; Ping et al., 2020; Ramadan et al., 2021; Soloviev & Kizub, 2019; Wang, Boerma & Zhou, 2016). 

Brain cells: oxidative stress can induce alterations to various pathways such as the PI3K/Akt pathway, cAMP response element- binding protein (CREB) pathway, the p53/p21 pathway, as well as the MAPK family pathways, including JNK, ERK and p38 (Lehtinen & Bonni, 2006; Ramalingam & Kim, 2012). 

Additionally, the electron transport chain in the mitochondria is an important source of ROS, which can damage mitochondria by inducing mutations in mitochondrial DNA. These mutations lead to mitochondrial dysfunction due to alterations in cellular respiration mechanisms that perpetuates oxidative stress and can then induce the release of signaling molecules related to apoptosis from the mitochondria. Pro-apoptotic markers (Bax, Bak and Bad) and anti-apoptotic markers (Bcl-2 and Bcl-xL) can regulate the caspase pathway that ultimately mediate apoptosis (Annunziato et al., 2003; Wang & Michaelis, 2010; Wu et al., 2019). 

The mechanisms of oxidative stress leading to altered signaling may be different for each pathway. For example, although both the PI3K/Akt and MAPK pathways can be regulated by insulin-like growth factor (IGF)-1, ROS results in selective inhibition of the IGF- 1R/PI3K/Akt pathway by inhibiting the IGF-1 receptor (IGF-1R) activation of IRS1 (Ping et al., 2020). Additionally, ROS-induced MAPK activation can be done through Ras-dependent signaling. Firstly, oxygen radicals mediate the phosphorylation of upstream epidermal growth factor receptors (EGFRs) on tyrosine residues, resulting in increased binding of growth factor receptor-bound protein 2 (Grb2) and subsequent activation of Ras signaling (Lehtinen & Bonni, 2006). Direct inhibition of MAPK phosphatases with hydroxyl radicals also activates this pathway (Li et al., 2013). In another mechanism, ROS competitively inhibit the Wnt/β-catenin pathway through the activation of forkhead box O (FoxO), which are involved in the antioxidant response and require binding of β- catenin for transcriptional activity (Tian et al., 2017). 

Evidence for this relationship was collected from studies using in vivo mouse, rat, and pig models, as well as in vitro mouse-derived, rat-derived, bovine-derived, and human-derived models. The stressors used to support this relationship include gamma rays, X rays, microgravity, hydrogen peroxide, chronic cold stress, heavy ion radiation, simulated ischemic stroke and growth differentiation factor (GDF) 15 overexpression. These stressors were shown to increase levels of oxidative stress and induce changes within relevant signaling pathways (Azimzadeh et al., 2021; Azimzadeh et al., 2015; Fan et al., 2017; Xu et al., 2019; Suman et al., 2013; Limoli et al., 2004; Tian et al., 2020; Hladik et al., 2020; ; Hasan, Radwan & Galal, 2019; El-Missiry et al., 2018; Kenchegowda et al., 2018; ; \, Zhao et al., 2013; Chen et al., 2009; Carvour et al., 2008; Wortel et al., 2019; Azimzadeh et al., 2017; Park et al., 2016; Sakata et al., 2015; Ruffels et al., 2004; Crossthwaite et al., 2002). 

Incidence concordance 

A few studies demonstrate greater changes to oxidative stress than to altered signaling. Human umbilical vein endothelial cells (HUVECs) irradiated with 10 Gy of X-rays showed a 20-fold increase in ROS and a 0.5-fold decrease in the ratio of p-Akt/Akt (Sakata et al., 2015). It was also shown in rats that MDA levels increased by 1.5-fold while angiotensin and aldosterone increased by 1.4-fold after 6 Gy of gamma rays (Hasan, Radwan & Galal, 2020).  

Dose Concordance 

Many studies demonstrate dose concordance for this relationship, at the same doses. Low-dose (0.5 Gy) X-ray irradiation of human coronary artery endothelial cells (HCAECs) show increased protein carbonylation with decreased glutathione S-transferase omega- 1 (GSTO1) antioxidant levels and a simultaneous alteration of signaling proteins Rho GDP-dissociation inhibitor (RhoGDI), p16, and p21 (Azimzadeh et al., 2017). A dose of about 2 Gy of gamma rays showed decreased antioxidants as well as decreased protein levels and activation of the PI3K/Akt pathway in pig cardiac tissue (Kenchegowda et al., 2018). Similarly, gamma irradiation at 6 Gy resulted in reduced levels of the antioxidant glutathione (GSH) and increased levels of the lipid peroxidation marker MDA as well as an increase in the renin angiotensin aldosterone system (RAAS) measured in rat heart tissue and blood serum, respectively (Hasan, Radwan & Galal, 2020). HUVECs irradiated with 10 Gy of X-rays demonstrated increased ROS while p-Akt decreased and p-ERK1/2 increased (Sakata et al., 2015). Gamma radiation at 15 Gy led to both increased ROS as well as attenuated p38 MAPK and Nrf2 signaling pathways in murine cardiac tissue (Fan et al., 2017). In contrast, 16 Gy X-ray exposure led to decreased levels of the antioxidant SOD, increased MDA as well as increased MAPK signaling in murine heart tissue (Azimzadeh et al., 2021).  

In another study, X-ray irradiation at 16 Gy resulted in decreased SOD and increased MDA and protein carbonylation, which were associated with decreased PI3K/Akt pathway activity and protein levels, decreased ERK activity and protein levels, increased p38 activity, and increased p16 and p21 protein levels in heart tissue (Azimzadeh et al., 2015). Azimzadeh et al. (2015) also showed that at 8 Gy oxidative stress was still observed, but fewer signaling molecule levels and activity were altered at this. Particularly, no changes to MAPK pathways were observed. 

Within the rat hippocampus, El-Missiry et al. (2018) demonstrated that exposure to 4 Gy of X-irradiation results in increased 4-HNE (oxidative stress marker) levels, reduced antioxidant activity and an increase in p53 expression. In the cerebral cortex of mice, Suman et al. (2013) reported that 1.6 Gy of 56Fe and 2 Gy of gamma rays increased ROS levels, consequently increased p21 and p53 levels. Limoli et al. (2004) also reported increased ROS levels in mice and rat neural precursor cells after exposure to X- irradiation (1-10 Gy), accompanied by increased expression of p21 and p53. Hladik et al. (2020) exposed female mice to 0.063, 0.125 or 0.5 Gy of gamma-radiation, which resulted in increases of protein carbonylation, as well as increased phosphorylation of CREB, ERK1/2 and p38. Radiation-induced changes in apoptotic markers were also reported. More specifically, there was a significant rise in pro-apoptotic markers Bax and caspase 3, with significant reduction in anti-apoptotic marker Bcl-xL (Hladik et al., 2020). Furthermore, middle cerebral artery occlusion (MCAO) surgery known to simulate ischemic stroke in C57BL/6J mice was shown to increase ROS levels, as well as the phosphorylation of ERK1/2, p38 and JNK (Tian et al., 2020). 

Other studies that have used hydrogen peroxide (H2O2) to induce oxidative stress within cell cultures, have also observed alterations in signaling pathways. Zhao et al. (2013) exposed mouse hippocampal-derived HT22 cells to varying concentrations of H2O2 and found a dose-dependent increase in ROS production from 250-1000 µM. Additionally, treating the cells to H2O2 resulted in a concentration-dependent increase of ERK1/2, JNK1/2 and p38 phosphorylation. Ruffels et al. (2004) incubated human neuroblastoma cells (SH-SY5Y) to varying concentrations of H2O2 that ranged from 0.5-1.25 mM and found a dose-dependent increase in JNK1/2, ERK1/2 and Akt phosphorylation. Another study exposed SH-SY5Y and rat pheochromocytoma (PC12) cells to 0.05-2 mM H2O2 and found a dose-dependent increase in ROS from 0-1 mM in SH-SY5Y cells, and from 0-2 mM in PC12 cells with a concentration-dependent increase in ERK1/2, p38 and JNK phosphorylation (Chen et al., 2009). Furthermore, Crossthwaite et al. (2002) incubated neuronal cultures from 15- to 16-day-old Swiss mice to 100, 300 and 1000 µm H2O2 and showed increased levels of ROS. A corresponding increase in ERK1/2 and Akt activation was observed at 100-300 µm, and for JNK1/2 the observation was observed at 1000 µm. Carvour et al. (2008) treated N27 cells (rat dopaminergic cell line) to 3-30 µM H2O2 and measured increased ROS levels, as well as increased apoptotic signaling molecules caspase 3 and proapoptotic kinase protein kinase C-δ (PKCδ) cleavage. 

Time Concordance 

Limited evidence shows that oxidative stress leads to altered stress response signalling in a time concordant manner. When irradiated with X-rays, HCAECs, BAECs and MCT3T3-E1 osteoblast-like cells show increase in ROS or levels of protein carbonylation, or a decrease in the levels of superoxide dismutase (SOD), catalase (CAT), GSTO1 or GSH at earlier timepoints than alterations in the signaling molecules p16, p21, Ceramide, Runx2, and HO-1 (Azimzadeh et al., 2017; Kook et al., 2015; Wortel et al., 2019). As the key events are both molecular-level changes, both can occur quickly after irradiation. Wortel et al. (2019) found that increased hydrogen peroxide levels could be observed in vitro as early as 2 minutes post-irradiation, while ASMase activity and ceramide levels were only increased 5 minutes post-irradiation. 

When exposed to H2O2, PC12 cells show an increase production of ROS with a corresponding increase in phosphorylation of MAPK proteins in a time-dependent fashion. An increase in ERK1/2, JNK and p38 phosphorylation was observed within 5-15 minutes and sustained for over 2 hours (Chen et al., 2009). When exposed to cold stress for 1, 2 and 3 weeks, MDA levels increased in a time-dependent manner from 1-3 weeks within the brain tissue isolated from C57BL/6 mice. The expressions of JNK, ERK and p38 phosphorylation levels were all also significantly upregulated in chronic cold-stressed groups for all time-points (Xu et al., 2019). After gamma irradiation (2 Gy), ROS increased 2 months post-irradiation, while increased p21 and decreased Bcl-2 were only observed at 12 months (Suman et al., 2013). However, other signaling molecules were increased at both times. 

Essentiality 

Several studies have investigated the essentiality of the relationship, where the blocking or attenuation of the upstream KE causes a change in frequency of the downstream KE. The increase in oxidative stress can be modulated by certain drugs, antioxidants and media. L-carnitine injections decreased ROS and increased p-p38/p38 and p-Nrf2/Nrf2 signaling (Fan et al., 2017). Fenofibrate was found to return SOD, phosphorylated MAPK signaling proteins and increase Nrf2 levels (Azimzadeh et al., 2021). Antioxidants (N- acetyl cysteine, curcumin) were shown to restore or reduce ROS levels closer to control levels following radiation or microgravity exposure, respectively. . Sildenafil is another drug that was found to reduce ROS generation by inhibiting O2- production and intracellular peroxynitrite levels in bovine aortic endothelial cells (BAECs) after gamma irradiation. As well, ASMase activity and ceramide levels were inhibited by sildenafil (Wortel et al., 2019). 

Within brain cells, several antioxidants have been found to attenuate oxidative stress-induced alterations in signaling pathways. These antioxidants include Melandrii Herba extract, N-acetyl-L-cysteine (NAC), gallocatechin gallate/epigallocatechin-3-gallate, Cornus officinalis (CC) and fermented CC (FCC), L-165041, fucoxanthin, and edaravone. These antioxidants were shown to reduce ROS and subsequently decrease phosphorylation of MAPKs such as ERK1/2, JNK1/2 and p38 after exposure to radiation, H2O2 or LPS (Lee et al., 2017; Deng et al., 2012; Park et al., 2021; Tian et al., 2020; Schnegg et al., 2012; Zhao et al., 2017; Zhao et al., 2013; El-Missiry et al., 2018). Another documented modulator is mesenchymal stem-cell conditioned medium (MSC-CM), which was able to alleviate oxidative stress in HT22 cells and restore levels of p53 (Huang et al., 2021). 

• MAPK pathways can exhibit varied responses after exposure to oxidative stress. The expected response is an increase in the activity of the ERK, JNK, and p38 pathways as protein phosphatases, involved in the inactivation of MAPK pathways, are deactivated by oxidative stress (Valerie et al., 2007). Although some studies observe this (Azimzadeh et al., 2021; Sakata et al., 2015), others show a decrease (Fan et al., 2017) or varying changes (Azimzadeh et al., 2015) in the MAPK pathways. 

  The assays employed in studies to assess the KEs may lead to variations in the quantitative understanding of observations. 

Quantitative Understanding of the Linkage

The tables below provide representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data that is represented is statistically significant unless otherwise indicated. 

Dose/Incidence Concordance 

Time Concordance 

ROS can upregulate protein kinase C, which stimulates the production of ceramide from sphingomyelinase. Ceramide activates NADPH oxidase, which can then produce more ROS (Soloviev & Kizub, 2019). Another feedback loop exists between the Nrf2/HO-1 signaling pathway and oxidative stress. The Nrf2/HO-1 signaling pathway is involved in negative feedback of oxidative stress, activating transcription of anti-oxidative enzymes to regulate cellular ROS and maintain a redox balance (Tahimic & Globus, 2017; Tian et al., 2017). Lastly, the MAPK pathway also exhibits a feedback loop. ERK can regulate ROS levels indirectly through p22phox, which increases ROS and upregulates antioxidants by Nrf2 activation. JNK activation can lead to FoxO activation, thereby resulting in antioxidant production (Arfin et al., 2021; Essers et al., 2004). 

References

Annunziato, L. (2003), "Apoptosis induced in neuronal cells by oxidative stress: role played by caspases and intracellular calcium ions", Toxicology Letters, Vol. 139/2–3, https://doi.org/10.1016/S0378-4274(02)00427-7. 

Arfin, S. et al. (2021), “Oxidative Stress in Cancer Cell Metabolism”, Antioxidants 2021, Vol. 10/5, MDPI, Basel, https://doi.org/10.3390/ANTIOX10050642 

Azimzadeh, O. et al. (2021), "Activation of pparα by fenofibrate attenuates the effect of local heart high dose irradiation on the mouse cardiac proteome", Biomedicines, Vol. 9/12, MDPI, Basel, https://doi.org/10.3390/biomedicines9121845 

Azimzadeh, O. et al. (2017), "Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways", International Journal of Radiation Biology, Vol. 93/9, Informa, London, https://doi.org/10.1080/09553002.2017.1339332 

Azimzadeh, O. et al. (2015), "Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction", Journal of Proteome Research, Vol. 14/2, American Chemical Society, Washington, https://doi.org/10.1021/pr501141b 

Boyce, B. F. and L. Xing. (2007), "The RANKL/RANK/OPG pathway", Current Osteoporosis Reports, Vol. 5/3, https://doi.org/10.1007/s11914-007-0024-y 

Cabrera, M. P. and R. H. Chihuailaf. (2011), "Antioxidants and the Integrity of Ocular Tissues", Veterinary Medicine International, Vol. 2011, Hindawi, London, https://doi.org/10.4061/2011/905153 

Carvour, M. et al. (2008), "Chronic Low-Dose Oxidative Stress Induces Caspase-3-Dependent PKCδ Proteolytic Activation and Apoptosis in a Cell Culture Model of Dopaminergic Neurodegeneration", Annals of the New York Academy of Sciences, Vol. 1139/1, https://doi.org/10.1196/annals.1432.020. 

Chen, L. et al. (2009), "Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway", The International Journal of Biochemistry & Cell Biology, Vol. 41/6, Elsevier, Amsterdam, https://doi.org/10.1016/j.biocel.2008.10.029. 

Crossthwaite, A. J., S. Hasan and R. J. Williams. (2002), "Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca2+ and PI3-kinase", Journal of Neurochemistry, Vol. 80/1, John Wiley & Sons, Hoboken, https://doi.org/10.1046/j.0022-3042.2001.00637.x. 

Deng, Z. et al. (2012), "Radiation-Induced c-Jun Activation Depends on MEK1-ERK1/2 Signaling Pathway in Microglial Cells", (I. Ulasov, Ed.) PLoS ONE, Vol. 7/5, https://doi.org/10.1371/journal.pone.0036739. 

El-Missiry, M. A. et al. (2018), "Neuroprotective effect of epigallocatechin-3-gallate (EGCG) on radiation-induced damage and apoptosis in the rat hippocampus", International Journal of Radiation Biology, Vol. 94/9, https://doi.org/10.1080/09553002.2018.1492755. 

Fan, Z. et al. (2017), "L-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation", European Journal of Pharmacology, Vol. 804, Elsevier, Amsterdam, https://doi.org/10.1016/j.ejphar.2017.04.003 

Hasan, H. F., R. R. Radwan and S. M. Galal. (2020), "Bradykinin‐potentiating factor isolated from Leiurus quinquestriatus scorpion venom alleviates cardiomyopathy in irradiated rats via remodelling of the RAAS pathway", Clinical and Experimental Pharmacology and Physiology, Vol. 47/2, Wiley, https://doi.org/10.1111/1440-1681.13202 

Hladik, D. et al. (2020), "CREB Signaling Mediates Dose-Dependent Radiation Response in the Murine Hippocampus Two Years after Total Body Exposure", Journal of Proteome Research, Vol. 19/1, https://doi.org/10.1021/acs.jproteome.9b00552. 

Huang, Y. et al. (2021), "Mesenchymal Stem Cell-Conditioned Medium Protects Hippocampal Neurons From Radiation Damage by Suppressing Oxidative Stress and Apoptosis", Dose-Response, Vol. 19/1, https://doi.org/10.1177/1559325820984944. 

Hughson, R. L., A. Helm and M. Durante. (2018), "Heart in space: Effect of the extraterrestrial environment on the cardiovascular system", Nature Reviews Cardiology, Vol. 15/3, Nature, https://doi.org/10.1038/nrcardio.2017.157 

Kenchegowda, D. et al. (2018), "Selective Insulin-like Growth Factor Resistance Associated with Heart Hemorrhages and Poor Prognosis in a Novel Preclinical Model of the Hematopoietic Acute Radiation Syndrome", Radiation Research, Vol. 190/2, BioOne, https://doi.org/10.1667/RR14993.1 

Kozbenko, T. et al. (2022), “Deploying elements of scoping review methods for adverse outcome pathway development: a space travel case example”, International Journal of Radiation Biology, Vol. 98/12. https://doi.org/10.1080/09553002.2022.2110306 

Lee, K., A. Lee and I. Choi. (2017), "Melandrii Herba Extract Attenuates H2O2-Induced Neurotoxicity in Human Neuroblastoma SH- SY5Y Cells and Scopolamine-Induced Memory Impairment in Mice", Molecules, Vol. 22/10, MDPI, Basel, https://doi.org/10.3390/molecules22101646. 

Lehtinen, M. and A. Bonni. (2006), "Modeling Oxidative Stress in the Central Nervous System", Current Molecular Medicine, Vol. 6/8, https://doi.org/10.2174/156652406779010786. 

Li, J. et al. (2013), "Oxidative Stress and Neurodegenerative Disorders", International Journal of Molecular Sciences, Vol. 14/12, https://doi.org/10.3390/ijms141224438. 

Limoli, C. L. et al. (2004), "Radiation Response of Neural Precursor Cells: Linking Cellular Sensitivity to Cell Cycle Checkpoints, Apoptosis and Oxidative Stress", Radiation Research, Vol. 161/1, https://doi.org/10.1667/RR3112. 

Essers, M. A. et al. (2004), “FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK”. The EMBO journal, Vol. 23/24, EMBO, https://doi.org/10.1038/sj.emboj.7600476 

Nagane, M. et al. (2021), "DNA damage response in vascular endothelial senescence: Implication for radiation-induced cardiovascular diseases", Journal of Radiation Research, Vol. 62/4, Oxford University Press, Oxford, https://doi.org/10.1093/jrr/rrab032 

Park, H. et al. (2016), "GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells", Oncotarget, Vol. 7/9, https://doi.org/10.18632/oncotarget.7457 

Park, D. H. et al. (2021), "Neuroprotective Effect of Gallocatechin Gallate on Glutamate-Induced Oxidative Stress in Hippocampal HT22 Cells", Molecules, Vol. 26/5, MDPI, Basel, https://doi.org/10.3390/molecules26051387. 

Ping, Z. et al. (2020), "Oxidative Stress in Radiation-Induced Cardiotoxicity", Oxidative Medicine and Cellular Longevity, Vol. 2020, Hindawi, London, https://doi.org/10.1155/2020/3579143 

Ramadan, R. et al. (2021), "The role of connexin proteins and their channels in radiation-induced atherosclerosis", Cellular and Molecular Life Sciences, Vol. 78, Nature, https://doi.org/10.1007/s00018-020-03716-3 

Ramalingam, M. and S.-J. Kim. (2012), "Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases", Journal of Neural Transmission, Vol. 119/8, Springer Nature, Berlin, https://doi.org/10.1007/s00702-011-0758-7. 

Ruffels, J., M. Griffin and J. M. Dickenson. (2004), "Activation of ERK1/2, JNK and PKB by hydrogen peroxide in human SH-SY5Y neuroblastoma cells: role of ERK1/2 in H2O2-induced cell death", European Journal of Pharmacology, Vol. 483/2–3, Elsevier, Amsterdam https://doi.org/10.1016/j.ejphar.2003.10.032. 

Sakata, K. et al. (2015), "Roles of ROS and PKC-βII in ionizing radiation-induced eNOS activation in human vascular endothelial cells", Vascular Pharmacology, Vol. 70, Elsevier, Amsterdam, https://doi.org/10.1016/j.vph.2015.03.016 

Schmidt-Ullrich, R. K. et al. (2000), "Signal transduction and cellular radiation responses.", Radiation research, Vol. 153/3, BioOne,https://doi.org/10.1667/00337587(2000)153[0245:stacrr]2.0.co;2 

Schnegg, C. I. et al. (2012), "PPARδ prevents radiation-induced proinflammatory responses in microglia via transrepression of NF- κB and inhibition of the PKCα/MEK1/2/ERK1/2/AP-1 pathway", Free Radical Biology and Medicine, Vol. 52/9, https://doi.org/10.1016/j.freeradbiomed.2012.02.032. 

Soloviev, A. I. and I. V. Kizub. (2019), "Mechanisms of vascular dysfunction evoked by ionizing radiation and possible targets for its pharmacological correction", Biochemical Pharmacology, Vol. 159, Elsevier, Amsterdam, https://doi.org/10.1016/j.bcp.2018.11.019 

Suman, S. et al. (2013), "Therapeutic and space radiation exposure of mouse brain causes impaired DNA repair response and premature senescence by chronic oxidant production", Aging, Vol. 5/8, https://doi.org/10.18632/aging.100587. 

Sun, Y. et al. (2013), "Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats", Osteoporosis International, Vol. 24/3, Nature, https://doi.org/10.1007/s00198-012-2028-4 

Tahimic, C. G. T. and R. K. Globus. (2017), “Redox Signaling and Its Impact on Skeletal and Vascular Responses to Spaceflight”, International Journal of Molecular Sciences, Vol. 18/10, MDPI, Basel, https://doi.org/10.3390/IJMS18102153 

Tian, Y. et al. (2017), "The impact of oxidative stress on the bone system in response to the space special environment", International Journal of Molecular Sciences, Vol. 18/10, MDPI, Basel, https://doi.org/10.3390/ijms18102132 

Tian, W. et al. (2019), "Neuroprotective Effects of Cornus officinalis on Stress-Induced Hippocampal Deficits in Rats and H2O2- Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells", Antioxidants, Vol. 9/1, MDPI, Basel, https://doi.org/10.3390/antiox9010027. 

Tian, R. et al. (2020), "miR-137 prevents inflammatory response, oxidative stress, neuronal injury and cognitive impairment via blockade of Src-mediated MAPK signaling pathway in ischemic stroke", Aging, Vol. 12/11, https://doi.org/10.18632/aging.103301. 

Valerie, K. et al. (2007), "Radiation-induced cell signaling: inside-out and outside-in", Molecular Cancer Therapeutics, Vol. 6/3, American Association for Cancer Research, https://doi.org/10.1158/1535-7163.MCT-06-0596 

Venkatesulu, B. P. et al. (2018), “Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms”, JACC: Basic to translational science, Vol. 3/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.jacbts.2018.01.014. 

Wang. (2010), "Selective neuronal vulnerability to oxidative stress in the brain", Frontiers in Aging Neuroscience, https://doi.org/10.3389/fnagi.2010.00012. 

Wang, Y., M. Boerma and D. Zhou. (2016), "Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases", Radiation Research, Vol. 186/2, BioOne, https://doi.org/10.1667/RR14445.1 

Wortel, R. C. et al. (2019), "Sildenafil Protects Endothelial Cells From Radiation-Induced Oxidative Stress", The Journal of Sexual Medicine, Vol. 16/11, Elsevier, Amsterdam, https://doi.org/10.1016/j.jsxm.2019.08.015 

Wu, Y., M. Chen and J. Jiang. (2019), "Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling", Mitochondrion, Vol. 49, https://doi.org/10.1016/j.mito.2019.07.003. 

Xu, B. et al. (2019), "Oxidation Stress-Mediated MAPK Signaling Pathway Activation Induces Neuronal Loss in the CA1 and CA3 Regions of the Hippocampus of Mice Following Chronic Cold Exposure", Brain Sciences, Vol. 9/10, MDPI, Basel, https://doi.org/10.3390/brainsci9100273. 

Zhao, Z.-Y. et al. (2013), "Edaravone Protects HT22 Neurons from H 2 O 2 -induced Apoptosis by Inhibiting the MAPK Signaling Pathway", CNS Neuroscience & Therapeutics, Vol. 19/3, John Wiley & Sons, Hoboken, https://doi.org/10.1111/cns.12044. 

Zhao, D. et al. (2017), "Anti-Neuroinflammatory Effects of Fucoxanthin via Inhibition of Akt/NF-κB and MAPKs/AP-1 Pathways and Activation of PKA/CREB Pathway in Lipopolysaccharide-Activated BV-2 Microglial Cells", Neurochemical Research, Vol. 42/2, Springer Nature, Berlin, https://doi.org/10.1007/s11064-016-2123-6 

Relationship: 2833: Oxidative Stress leads to Tissue resident cell activation

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Evidence for this relationship comes from in vitro human- and mouse-derived models, as well as in vivo rat models. Most of the evidence are in male adult and male models, although sex and age are not always specified.  

Key Event Relationship Description

Oxidative stress encompasses an increase in the production of free radicals (e.g., superoxide, hydrogen peroxide and hydroxyl radicals) and a loss of antioxidant mechanisms (e.g., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT)). This imbalance can lead to damaging by-products that can activate tissue resident cells. Reactive oxygen and nitrogen species (RONS) are examples of free radicals that may promote oxidative injury (Simpson & Oliver, 2020). In addition, excess free radicals can promote a reduced capacity of the cells to maintain redox balance and prevent ongoing oxidative damage (Huang, Zou & Corniola, 2012; Rojo et al., 2014). Depending on the organ/tissue, different resident cell types may become activated by oxidative stress. For example, in the brain, oxidative stress will specifically activate microglial cells and astrocytes (Lee, Cha & Lee, 2021). Microglia cells are macrophages in the brain that respond to tissue injury, provide surveillance to neurons, and maintain synaptic homeostasis (Zhu et al., 2022). Astrocytes are critical regulators of neurogenesis and synaptogenesis, blood brain barrier permeability, and responsible for maintenance of cellular homeostasis (Zhu et al., 2022). Both microglial cells and astrocytes can change from resting to reactive states, termed gliosis, in response to excess RONS (Lee, Cha & Lee, 2021). In response to RONS, Toll like receptors (TLRs) located on microglia become activated to mediate the immune response (Gill et al., 2010; Mehdipour et al., 2021). These receptors then initiate a cascade of signaling pathways that contribute to the production of pro-inflammatory cytokines and free radicals, resulting in neuroinflammation (Heidari et al., 2022). 

Reactive microglia cells increase in size and number, display a reduction in the length and density of their processes, and upregulate their macrophagic processes, marked by expression of proteins related to phagocytic activity such as cluster of differentiation 68 (CD68) (Hol & Pekny, 2015). Astrocytes undergoing astrogliosis exhibit cellular hypertrophy and an upregulation of glial fibrillary acidic protein (GFAP), an intermediate filament expressed exclusively in astrocytes that plays a critical role in astroglia cell activation (Hol & Pekny, 2015). Activation of both microglial cells and astrocytes can accelerate neuroinflammatory pathways that can ultimately promote further formation of ROS creating a feedforward loop (Lee, Cha & Lee, 2021; Simpson & Oliver, 2020; Zhu et al., 2022).  

Evidence Supporting this KER

Overall Weight of Evidence: Moderate 

Biological Plausibility is Moderate. RONS can activate some inflammatory and anti-inflammatory pathways (TLR, TGF-β, NF-kB), and are an essential part of multiple inflammatory and anti-inflammatory pathways (TLR4, TNF-a, TGF-β, NF-kB). 

RONS activates or is essential to many inflammatory pathways including TGF-β (Barcellos-Hoff and Dix 1996; Jobling, Mott et al. 2006), TNF (Blaser, Dostert et al. 2016), Toll-like receptor (TLR) (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Miller, Goodson et al. 2017; Cavaillon 2018), and NF-kB signaling (Gloire, Legrand-Poels et al. 2006; Morgan and Liu 2011). These interactions principally involve ROS, but RNS can indirectly activate TLRs and possibly NF-kB. Since inflammatory signaling and activated immune cells can also increase the production of RONS, positive feedback and feedforward loops can occur (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016). 

Damage inflicted by RONS on cells activate TLRs and other receptors to promote release of cytokines (Ratikan, Micewicz et al. 2015). For example, oxidized lipids or oxidative stress-induced heat shock proteins can activate TLR4 (Miller, Goodson et al. 2017; Cavaillon 2018). 

ROS is essential to TLR4 activation of downstream signals including NF-kB. Activation of TLR4 promotes the surface expression and movement of TLR4 into signal-promoting lipid rafts (Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). This signal promotion requires NADPH-oxidase and ROS (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006). ROS is also required for the TLR4/TRAF6/ASK-1/p38 dependent activation of inflammatory cytokines (Matsuzawa, Saegusa et al. 2005). ROS therefore amplifies the inflammatory process. 

RONS can also fail to activate or actively inhibit inflammatory pathways, and the circumstances determining response to RONS are not well known (Gloire, Legrand-Poels et al. 2006). 

Responses to oxidative stress can vary depending on the organ system. In the central nervous system (CNS), biological plausibility supporting the connection between increased oxidative stress to tissue resident cell activation is moderately supported by evidence compiled from studies using animal and in vitro models. Multiple studies have shown that microglial cells and astrocytes are activated in response to RONS, meaning they change from resting to reactive states by secreting pro-inflammatory mediators and initiating antioxidant defenses mediated through TLRs (Simpson & Oliver, 2020; Heidari et al., 2022). Literature reviews describing the role of oxidative stress imbalances and glial cell activation in the context of general oxidative injury (Lee, Cha & Lee, 2021), stroke (Zhu et al., 2022) and neurodegenerative diseases (Reynolds et al., 2007; Simpson & Oliver, 2020) also suggest a relationship between increased oxidative stress and increased tissue resident cell activation in the CNS.

Empirical Evidence is Moderate. Both RONS and inflammation increase in response to agents that increase RONS or inflammation, and antioxidants reduce inflammation. Multiple studies show dose-dependent changes in both RONS and inflammation in response to stressors including ionizing radiation and antioxidants. RONS have been measured at the same or earlier time points as inflammatory markers, but additional studies are needed to characterize the inflammatory response at the earliest time points to support causation. Uncertainties come from the positive feedback from inflammation to RONS potentially interfering with attempts to establish causality, and from the large number of inflammation-related endpoints with differing responses to stressors and experimental variation. 

Oxidative activity is required for or promotes the response to multiple inflammatory stressors, including ionizing radiation, UV radiation (particularly UVB), the endotoxin LPS and other pathogens associated immune activators, and hemorrhagic shock (Park, Jung et al. 2004; Nakahira, Kim et al. 2006; Powers, Szaszi et al. 2006; Zhao and Robbins 2009; Ha, Chung et al. 2010; Hiramoto, Kobayashi et al. 2012; Straub, New et al. 2015).  

Both intracellular concentrations of RONS and a wide range of inflammatory markers increase in response to RONS stressors. This paired increase was observed in vivo in rodents in tissue from multiple internal organs following exposure to whole body or abdominal ionizing radiation (Berruyer, Martin et al. 2004; Ha, Chung et al. 2010; Sinha, Das et al. 2011; Sinha, Das et al. 2012; Das, Manna et al. 2014; Ozyurt, Cevik et al. 2014; Khan, Manna et al. 2015; Zetner, Andersen et al. 2016; Haddadi, Rezaeyan et al. 2017; Ezz, Ibrahim et al. 2018) or following UV skin irradiation (Sharma, Meeran et al. 2007; Hiramoto, Kobayashi et al. 2012; Martinez, Pinho-Ribeiro et al. 2016). In vitro, the relationship has been reported in response to IR and UV in keratinocytes (Park, Ju et al. 2006; Kang, Kim et al. 2007; Martin, Sur et al. 2008; Lee, Jeon et al. 2010; Ren, Shi et al. 2016; Hung, Tang et al. 2017; Zhang, Zhu et al. 2017), immune cells (Matsuzawa, Saegusa et al. 2005; Nakahira, Kim et al. 2006; Manna, Das et al. 2015; Soltani, Ghaemi et al. 2016), as well as corneal and conjunctival epithelia, HEK cells, and vocal cord and foreskin fibroblasts (Narayanan, LaRue et al. 1999; Park, Jung et al. 2004; Saltman, Kraus et al. 2010; Black, Gordon et al. 2011; Han, Min et al. 2015). Direct application of micromolar concentrations of H2O2 in vitro also increases inflammatory markers in immune cells (Matsuzawa, Saegusa et al. 2005; Nakao, Kurokawa et al. 2008) and keratinocytes (Zhang, Zhu et al. 2017). 

Interventions to reduce oxidative activity also reduce inflammation, further implicating RONS in the inflammatory process. Reduction of inflammation by these interventions has been documented in animals in response to IR (Berruyer, Martin et al. 2004; Sinha, Das et al. 2011; Sinha, Das et al. 2012; Das, Manna et al. 2014; Ozyurt, Cevik et al. 2014; Khan, Manna et al. 2015; Zetner, Andersen et al. 2016; Haddadi, Rezaeyan et al. 2017; Ezz, Ibrahim et al. 2018), UV (Sharma, Meeran et al. 2007; Lee, Jeon et al. 2010; Hiramoto, Kobayashi et al. 2012; Han, Min et al. 2015; Martinez, Pinho-Ribeiro et al. 2016; Ren, Shi et al. 2016; Hung, Tang et al. 2017) and hemorrhagic shock (Powers, Szaszi et al. 2006). In vitro, multiple studies in immune cells (Matsuzawa, Saegusa et al. 2005; Nakahira, Kim et al. 2006; Manna, Das et al. 2015; Soltani, Ghaemi et al. 2016) and keratinocytes (Park, Ju et al. 2006; Kang, Kim et al. 2007; Martin, Sur et al. 2008; Lee, Jeon et al. 2010; Ren, Shi et al. 2016; Hung, Tang et al. 2017; Zhang, Zhu et al. 2017) as well as HEK293, fibroblasts, and epithelial cells (Lee, Dimtchev et al. 1998; Narayanan, LaRue et al. 1999; Park, Jung et al. 2004; Han, Min et al. 2015) provide further evidence for reduction in various inflammatory markers with interventions to reduce RONS. Interventions include antioxidants such as propyl gallate, n-acetylcysteine, or naringin, as well as reduction in the function of NADPH oxidases (NOX/DUOX) via DPI or knockdown of gene expression. In studies using multiple doses of antioxidant, inflammation was reduced dose-dependently with the antioxidant dose (Nakahira, Kim et al. 2006; Manna, Das et al. 2015; Ren, Shi et al. 2016). Interventions reducing nitric oxide were not common, but in one study inhibiting iNOS did not reduce activation of NF- kB by IR (Lee, Dimtchev et al. 1998). The treatment to reduce RONS is administered before, or occasionally immediately after the inflammatory stressor, but studies often continue treatment or do not explicitly report changing media in vitro, so the exact time point at which RONS are required is difficult to pinpoint. 

IR and RONS decrease endogenous antioxidant activity (glutathione, superoxide dismutase, and catalase), and antioxidants rescue this suppression in antioxidant activity (Sharma, Meeran et al. 2007; Das, Manna et al. 2014). Mice with more endogenous glutathione have a lower inflammatory response to IR (Berruyer, Martin et al. 2004), suggesting that IR increases inflammation in part by decreasing antioxidants. 

In response to inflammatory stressors, RONS has been measured at the same (Nakao, Kurokawa et al. 2008; Ha, Chung et al. 2010; Saltman, Kraus et al. 2010; Azimzadeh, Scherthan et al. 2011; Ameziane-El-Hassani, Talbot et al. 2015; Azimzadeh, Sievert et al. 2015; Zhang, Zhu et al. 2017) or earlier time points as inflammatory markers (Nakahira, Kim et al. 2006; Black, Gordon et al. 2011). This suggests that RONS precedes the generation of inflammatory markers, consistent with a role for RONS in promoting inflammation. However, inflammatory markers are not typically measured at the earliest time points, and a more comprehensive survey of the appearance of these events at early time points would help to clarify the timeline and confirm the temporal evidence for causation.

A relatively small number of studies in a variety of cell types have examined both RONS and inflammatory markers across multiple doses. Three of these report dose-dependent increases in both RONS and inflammatory markers; one in which the key events are evaluated immediately after H2O2 application (Nakao, Kurokawa et al. 2008), and two others evaluated them 24 hours or 8-16 weeks after IR (Ha, Chung et al. 2010; Azimzadeh, Sievert et al. 2015). A fourth study reports a dose-dependent reduction in inflammation in response to treatment with antioxidants (Nakahira, Kim et al. 2006). In three other studies, some or all markers of inflammation increase at lower doses but decrease at higher doses (Saltman, Kraus et al. 2010; Black, Gordon et al. 2011; Zhang, Zhu et al. 2017). In two of these studies, RONS is also not consistently increasing with dose (Saltman, Kraus et al. 2010; Zhang, Zhu et al. 2017); however, this finding is consistent with findings from other studies about lack of dose-dependence of ROS measured at intermediate time points after IR. Similarly, 30 minutes after low dose, IR IL8 increases with dose while ROS does not (Narayanan, LaRue et al. 1999). The mixed inflammatory response at higher doses suggests that additional factors such as negative and positive feedback and crosstalk between pathways are also involved in the relationship between RONS and IR.

Dose Concordance 

Evidence to support this relationship in the brain is derived from studies using gamma rays (Schnegg et al., 2012), 6-OHDA (Wang et al., 2017), or H2O2 (Daverey & Agrawal, 2016) as the stressor. Oxidative stress and tissue resident cell activation were then assessed within the brain or glial cell cultures (Davery & Agrawal, 2016; Schnegg et al., 2012; Wang, 2017; Daverey & Agrawal, 2016; Schnegg et al., 2012; Wang et al., 2017). Few studies show that oxidative stress occurs at lower or the same dose of a stressor than tissue-resident cell activation. Treatment with 4 µg/µL of the neurotoxin 6-hydroxydopamine caused decreased antioxidant levels as well as increased glial fibrillary acidic protein (GFAP) levels in rats (Wang et al., 2017). In another study, astrocyte activation showed a slight linear increase in response to 50 µM, 100 µM and 200 µM of H2O2 (Daverey & Agrawal, 2016).

Time Concordance 

Few studies show that oxidative stress occurs before or at the same time as tissue-resident cell activation in a time course. BV-2 microglia irradiated with 10 Gy gamma rays showed an increase in ROS 1h post-irradiation, while an increase in NF-κB and AP-1 DNA binding was also observed 1h post-irradiation (Schnegg et al., 2012). Treatment of human glioblastoma astrocytes (A172 cell) with 50 µM of H₂O₂ for various times, showed a small linear increase in GFAP levels from 2h to 24h of treatment (Daverey & Agrawal, 2016).  

Incidence Concordance 

Schnegg et al. (2012) irradiated BV-2 microglia with gamma rays and showed increased ROS as well as increased NF-κB and AP-1 DNA binding, indicating activated glial cells, at the same dose of 10 Gy. 

Essentiality 

Studies examining the use of antioxidants to inhibit free radicals demonstrate the essentiality of oxidative stress and tissue resident cell activation. This has been observed in microglial cells using multiple types of inhibitors. In BV-2 microglia, activation of PPARδ (involved in anti-inflammatory responses) with the agonist L-16504, reduced formation of reactive oxygen species and microglial activation (Schnegg et al., 2012). Treatment with multiple doses of an antioxidant Kukoamine A (KuA) elicited a dose-dependent partial attenuation of radiation-induced markers of microglial cell activation in rats (Zhang et al. 2017). After administration of another antioxidant, curcumin, levels of SOD and GSH-Px were restored and GFAP levels were decreased (Daverey & Agrawal, 2016; Wang et al., 2017). Furthermore, a knockout model of mitochondrial SOD (SOD2) resulted in an increase in reactivity of microglial cells post-irradiation (Fishman et. al 2009). 

Although ROS can activate NF-KB (Gloire, Legrand-Poels et al. 2006), not all studies consistently show NF-kB activation after RONs stressor IR. It is possible that the link between ROS and NF-kB depends on the local environmental context, with different studies not adequately controlling all influential variables. One study offers a possible explanation based on temporal response: in macrophages, NF-kB was activated by shorter exposures to H2O2 (30 min), but the response disappeared with longer exposures (Nakao, Kurokawa et al. 2008). 

While many models in vivo and in vitro showed a decreased inflammatory response to RONS stressors IR in combination with antioxidants, in endothelial cells in culture the increase in IL6 and IL8 after IR was not reduced by antioxidants. Although a synergistic increase in those cytokines occurring with combined TNF-a and IR treatment was reduced by antioxidants (Meeren, Bertho et al. 1997). Multiple mechanisms can increase inflammation, that inflammatory factors participate in positive feedback loops, and that responses to stimuli vary between cells.

Many studies do not report direct measures of RONS. As RONS are quickly scavenged, the quantitative understanding of this relationship can be inconsistent, due to varied response of antioxidant enzymes across experimental conditions and time measurements.  

Limited data is available to support an understanding of this relationship at low doses (<0.1 Gy).

Quantitative Understanding of the Linkage

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated. 

Dose Concordance  

Time Concordance  

Incidence Concordance 

Since inflammatory signaling and activated immune cells can also increase the production of RONS, positive feedback and feedforward loops can occur (Zhao and Robbins 2009; Ratikan, Micewicz et al. 2015; Blaser, Dostert et al. 2016). Similarly, positive feedforward and feedback loops regarding RONS, cellular activation, and inflammation also occur in the CNS. Both RONS and microglial cell activation can accelerate neuroinflammatory pathways that can ultimately promote further formation of RONS (Lee, Cha & Lee, 2021; Simpson & Oliver, 2020; Zhu et al., 2022).  

References

Ávila‐Escalante, M. L. et al. (2020), "The effect of diet on oxidative stress and metabolic diseases—Clinically controlled trials", Journal of Food Biochemistry, Vol. 44/5, https://doi.org/10.1111/jfbc.13191. 

Daverey, A. and S. K. Agrawal. (2016), "Curcumin alleviates oxidative stress and mitochondrial dysfunction in astrocytes", Neuroscience, Vol. 333, https://doi.org/10.1016/j.neuroscience.2016.07.012. 

Fishman, K. et al. (2009), "Radiation-induced reductions in neurogenesis are ameliorated in mice deficient in CuZnSOD or MnSOD", Free Radical Biology and Medicine, Vol. 47/10, https://doi.org/10.1016/j.freeradbiomed.2009.08.016. 

Gill, R., A. Tsung and T. Billiar. (2010), "Linking oxidative stress to inflammation: Toll-like receptors", Free Radical Biology and Medicine, Vol. 48/9, https://doi.org/10.1016/j.freeradbiomed.2010.01.006. 

Hanslik, K. L., K. M. Marino and T. K. Ulland. (2021), "Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease", Frontiers in Cellular Neuroscience, Vol. 15, https://doi.org/10.3389/fncel.2021.718324. 

Heidari, A., N. Yazdanpanah and N. Rezaei. (2022), "The role of Toll-like receptors and neuroinflammation in Parkinson’s disease", Journal of Neuroinflammation, Vol. 19/1, https://doi.org/10.1186/s12974-022-02496-w. 

Hol, E. M. and M. Pekny. (2015), "Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system", Current Opinion in Cell Biology, Vol. 32, https://doi.org/10.1016/j.ceb.2015.02.004. 

Huang, T. T., Y. Zou and R. Corniola. (2012), "Oxidative stress and adult neurogenesis—Effects of radiation and superoxide dismutase deficiency", Seminars in Cell & Developmental Biology, Vol. 23/7, https://doi.org/10.1016/j.semcdb.2012.04.003. 

Kamceva, G. et al. (2016), "Cigarette Smoking and Oxidative Stress in Patients with Coronary Artery Disease", Open Access Macedonian Journal of Medical Sciences, Vol. 4/4, https://doi.org/10.3889/oamjms.2016.117. 

Lee, K. H., M. Cha and B. H. Lee. (2021), "Crosstalk between Neuron and Glial Cells in Oxidative Injury and Neuroprotection", International Journal of Molecular Sciences, Vol. 22/24, https://doi.org/10.3390/ijms222413315. 

Liguori, I. et al. (2018), "Oxidative stress, aging, and diseases", Clinical Interventions in Aging, Vol.13, https://doi.org/10.2147/CIA.S158513. 

Mehdipour, A. et al. (2021), "Ionizing radiation and toll like receptors: A systematic review article", Human Immunology, Vol. 82/6, https://doi.org/10.1016/j.humimm.2021.03.008. 

Reynolds, A. et al. (2007), "Oxidative Stress and the Pathogenesis of Neurodegenerative Disorders", International Review of Neurobiology, Vol. 82, https://doi.org/10.1016/S0074-7742(07)82016-2. 

Rojo, A. I. et al. (2014), "Redox Control of Microglial Function: Molecular Mechanisms and Functional Significance", Antioxidants & Redox Signaling, Vol. 21/12, https://doi.org/10.1089/ars.2013.5745. 

Schnegg, C. I. et al. (2012), "PPARδ prevents radiation-induced proinflammatory responses in microglia via transrepression of NF-κB and inhibition of the PKCα/MEK1/2/ERK1/2/AP-1 pathway", Free Radical Biology and Medicine, Vol. 52/9, Pergamon, https://doi.org/10.1016/J.FREERADBIOMED.2012.02.032. 

Simpson, D. S. A. and P. L. Oliver. (2020), "ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease", Antioxidants, Vol. 9/8, https://doi.org/10.3390/antiox9080743. 

Wang, Y. L. et al. (2017), "Protective Effect of Curcumin Against Oxidative Stress-Induced Injury in Rats with Parkinson’s Disease Through the Wnt/ β-Catenin Signaling Pathway", Cellular Physiology and Biochemistry, Vol. 43/6, https://doi.org/10.1159/000484302. 

Zhang, Y. et al. (2017), "Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1", Neurotoxicity Research, Vol. 31/2, https://doi.org/10.1007/s12640-016-9679-4. 

Zhu, G. et al. (2022), "Crosstalk Between the Oxidative Stress and Glia Cells After Stroke: From Mechanism to Therapies", Frontiers in Immunology, Vol. 13, https://doi.org/10.3389/fimmu.2022.852416. 

Relationship: 2834: Tissue resident cell activation leads to Increase, Pro-Inflammatory Mediators

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Evidence for this relationship comes from in vitro mouse- and human-derived models, as well as in vivo mouse and rat models. The relationship is not sex or life stage specific. 

Key Event Relationship Description

Tissue-resident cell activation refers to the stimulation of resident cells in organ systems. Tissue-resident immune cells can be found throughout the body, each tissue and organ containing specific resident immune cells (Chen et al., 2018; Gray & Farber, 2022). Monocytes, found in the blood, and macrophages, found in all tissues in the body, are the main components of the immune system (Ivanova & Orekhov, 2016). In the brain, the primary tissue-resident macrophages are microglia, while astrocytes are also important cells found in the brain (Bourgognon & Cavanagh, 2020; Greene-Schloesser et al., 2012; Wang et al., 2020). Activated tissue-resident cells can undergo gliosis, whereby they adopt a hypertrophic morphology and proliferate, exhibiting rounding of the cell body and retraction of cell processes (Greene-Schloesser et al., 2012; Phatnani & Maniatis, 2015). It is well-characterized that activated tissue-resident cells can increase expression of pro-inflammatory mediators (Hladik & Tapio, 2016; Lumniczky, Szatmari & Safrany, 2017; Kaur et al., 2019). Acute inflammation from controlled biosynthesis of pro-inflammatory mediators protects tissue and promotes healing (Kim & Joh, 2006; Vezzani & Viviani, 2015). Prolonged tissue-resident cell activation leads to dysregulation in production or secretion of pro-inflammatory mediators, which results in chronic inflammation and damage to tissue (Kim & Joh, 2006; Vezzani & Viviani, 2015). Additionally, activated tissue-resident cells can show increased levels of transcription factor nuclear factor κB (NF-κB) and activated protein 1 (AP-1) DNA binding due to increased oxidative stress or DNA damage (Betlazar et al., 2016; Lumniczky, Szatmari & Safrany, 2017). Through the activity of NF-κB, AP-1 and other signaling pathways, activated immune cells can together produce/secrete a variety of cytokines and chemokines (Betlazar et al., 2016; Chen et al., 2018; Greene-Schloesser et al., 2012; Kim & Joh, 2006; Phatnani & Maniatis, 2015; Smith et al., 2012; Wang et al., 2020). Chronic secretion of these inflammatory proteins can lead to downstream detriments, such as in the brain, altering blood-brain barrier permeability (Lumniczky, Szatmari & Safrany, 2017). 

Evidence Supporting this KER

Overall Weight of Evidence: Moderate 

Tissue-resident cells recognize pathogens or molecules released by injured or activated cells (Vezzani & Viviani, 2015). In response, resident cells become activated and release various pro-inflammatory mediators (Chen et al., 2018; Gray & Farber, 2022). There is an abundance of studies which explore this relationship using the brain microenvironment, where astrocytes and microglia are the primary tissue-resident cells. After activation, these cells increase in number (whether through proliferation or recruitment), undergo morphological changes and release cytokines (Greene-Schloesser et al., 2012; Kim & Joh, 2006). 

Several pathways and molecules are involved in the inflammatory response to activate tissue-resident cells. These molecules include certain pro-inflammatory cytokines and various inflammatory stimuli, such as lipopolysaccharide (LPS), thrombin (a protease), β-amyloid (Aβ), interferon (IFN)-γ, CD40 and gangliosides (Dheen, Kaur & Ling, 2007; Kim & Joh, 2006). For example, LPS can diffuse into brain parenchyma and activate microglia, which then expresses inflammatory mediators and ROS to initiate inflammation (Dheen, Kaur & Ling, 2007; Kim & Joh, 2006). As well, pattern recognition receptor activation, through molecules such as damage-associated molecular pattern molecules (DAMPs), can activate tissue-resident cells and, in turn, lead to pro-inflammatory mediator secretion (Chen et al., 2018). 

Once resident cells become activated, various pathways, including the NF-κB transcription factor pathway and the mitogen-activated protein kinase (MAPK)-AP-1 signaling pathway, can result in pro-inflammatory mediator production (Chen et al., 2018; Vezzani & Viviani, 2015; Wang et al., 2020). When activated, microglia and astrocytes are sources of cytokines in the central nervous system (CNS) (Bourgognon & Cavanagh, 2020; Kim & Joh, 2006; Smith et al., 2012; Vezzani & Viviani, 2015; Boyd et al., 2021). Furthermore, uniquely in the brain, astrocyte activation can lead to blood-brain barrier permeability through decreased astrocyte function, which can allow pro-inflammatory mediators to enter from the blood (Lumniczky, Szatmari & Safrany, 2017). 

An abundance of studies supports the connectivity of the two key events using activated glial cells in the brain microenvironment. Activated astrocytes express high levels of glial fibrillary acidic protein (GFAP) (Greene-Schloesser et al., 2012), while microglia activation results in the expression of OX-42, Iba1 (activated and non-activated), Mac-1, CD68, F4-80, Glut-5 and CR3/43. These markers play an important role in the phagocytic activity and morphological changes of activated microglia (Jurga, Paleczna & Kuter, 2020). Upon expression of these markers, cells release pro-inflammatory mediators, these can further activate other glial cells (Bourgognon & Cavanagh, 2020). This results in an inflammatory state, that initiates the further release of cytokines including IL-1 and TNF-⍺, IL-6, Cox-2 (Betlazar et al., 2016; Kim & Joh, 2006; Smith et al., 2012) and chemokines MCP-1 and ICAM-1 (Greene-Schloesser et al., 2012; Kyrkanides et al., 2002). Chronic activation of these cells can result in neurodegenerative disease due to their continuous release and the overexpression of potentially cytotoxic molecules, which may eventually lead to cognitive decline (Dheen, Kaur & Ling, 2007; Kaur et al., 2019; Smith et al., 2012). To suppress this activity, anti-inflammatory proteins need to be released such as tumor growth factor (TGF)-β and IL-10; these act to reduce neuron activity (Kim & Joh, 2006; Phatnani & Maniatis, 2015). In a state of chronic inflammation, the production of pro-inflammatory proteins increases, while anti-inflammatory proteins decrease, and this imbalance results in a reduced stress response (Jeon & Kim, 2016). 

The evidence supporting the relationship between tissue-resident cell activation leading to increased pro-inflammatory mediators was gathered from studies using human (Chen et al., 2016; Lodermann et al., 2012) and mouse (Dong et al., 2015; Komatsu et al., 2017; Liu et al., 2010; Ramanan et al., 2008; Scharpfenecker et al., 2012; van Neerven et al., 2010; Welser-Alves & Milner, 2013) in vitro cell cultures as well as rat (Lee et al., 2010; Liu et al., 2010; Zhou et al., 2017) and mouse (Dong et al., 2015; Kyrkanides et al. 2002; Parihar et al., 2018) in vivo models. The stressors used were gamma rays (Kyrkanides et al., 2002; Lee et al., 2010), X-rays (Liu et al., 2010; Lodermann et al., 2012; Scharpfenecker et al., 2012), 4He ions (Parihar et al., 2018), nominal photon energy (Zhou et al., 2017) and LPS treatment (Komatsu et al., 2017; van Neerven et al., 2010; Welser-Alves & Milner, 2013). Tissue-resident cell activation is assessed by examining the morphology of activated cells (Dong et al., 2015; Zhou et al., 2017) and the detection of activation markers (Chen et al., 2016; Dong et al., 2015; Liu et al., 2010; Parihar et al., 2018; Scharpfenecker et al., 2012; van Neerven et al., 2010; Welser-Alves & Milner, 2013; Zhou et al., 2017) and AP-1 and NF-κB DNA binding (Komatsu et al., 2017; Lee et al., 2010; Lodermann et al., 2012; Ramanan et al., 2008). Pro-inflammatory mediators, including cytokines, adhesion markers, and inflammatory enzymes were assessed at both the protein and mRNA level although transcriptional responses may not necessarily translate to changes in active signaling molecules. Such studies provide indirect evidence to support the relationship. 

Dose Concordance 

Many studies demonstrate that activation of tissue-resident cells occurs at lower or the same doses as increased pro-inflammatory mediators. Although, at doses of ionizing radiation less than 1 Gy, evidence suggests anti-inflammatory activation of macrophages instead of towards inflammation (Wu et al., 2017). This was shown after irradiation of human monocytes from 0.1 to 0.7 Gy which resulted in decreased NF-κB nuclear translocation and decreased IL-1β levels (Lodermann et al., 2012). Dong et al. (2015) used various models and endpoints to study this relationship. In vitro mouse microglia showed an activated morphology, increased F4-80 (activated macrophage indicator), and increased levels and expression of TNF-α and IL-1β all after 16 Gy X-rays (Dong et al., 2015). With the same stressor and dose but in mice kidneys, F4-80 and various pro-inflammatory cytokines were increased (Scharpfenecker et al., 2012). In vivo mice with 10 Gy cranial X-ray irradiation showed a similar response (Dong et al., 2015). Activation of glial cells in rat brains as well as levels of IL-1β and TNF-α in BV2 murine microglial cells increased linearly after 2, 4, 6, 8 and 10 Gy X-rays (Liu et al., 2010). Multiple studies found that LPS treatment at 1 µg/mL resulted in both macrophage activation and TNF-α production (Lodermann et al., 2012; Welser-Alves & Milner, 2013). Rats with 10 Gy gamma ray irradiation showed increases in both NF-κB and AP-1 DNA binding activity, indicators of activated microglia. At the same dose, pro-inflammatory mediators TNF-α, IL-1β and MCP-1 also increased (Lee et al., 2010).  When human microglia were irradiated with gamma rays, they showed a characteristic activated morphology after 8 Gy, while CR3/43 and Glut-5 (microglial activation markers) showed increased expression after 8 Gy, and IL-1α and TNF-α also showed increased expression after 8 Gy (Chen et al., 2016). 

Time Concordance 

Many studies observed that tissue-resident cell activation occurs earlier or at the same time as increased pro-inflammatory mediators. Mice irradiated with 4He particles showed increases in both activated microglia and pro-inflammatory chemokine CCL-3 after 1 year (Parihar et al., 2018). In vitro murine microglial cells and in vivo rat brains were irradiated with X-rays and showed increases in activated glial cells, as well as IL-1β and TNF-α pro-inflammatory mediators 24h post-irradiation (Liu et al., 2010). After mouse cranial X-ray irradiation, the number of F4-80 positive cells/mm2 was significantly increased from 3h to 2 weeks with a maximum after 24h, while TNF-α and IL-1β both showed significantly increased levels and expression at many times from 3h to 6 weeks post-irradiation, with maximum levels occurring after 24h (Dong et al., 2015). Gamma ray irradiation of rats showed increased NF-κB and AP-1 DNA binding at 4 and 8h after irradiation, with levels reduced to control after 24h, and mRNA and protein levels of pro-inflammatory mediators TNF-α, IL-1β and MCP-1 in the hippocampus and cerebellum showed a similar trend (Lee et al., 2010). Juvenile rats irradiated with 4MV photon energy showed that microglial density increased at 6 and 24 h post-irradiation in the external germinal layer of the cerebellum, while IL-1α, IL-1β, IL-6, IL-18, GRO/KC and CCL-2 were all significantly increased after 24h (Zhou et al., 2017). Human microglia irradiated with gamma rays showed a characteristic activated morphology after 7 days (Chen et al., 2016). In addition, activation markers CR3/43 and Glut-5 were expressed after 2 weeks and Glut-5 continued expression after 1 week and 10 days. IL-1α and TNF-α showed increased expression after 7 days, which was slightly lower after 2 weeks, but still significant (Chen et al., 2016). 

Incidence Concordance 

Two studies identified an incidence-concordant relationship between tissue resident cell activation and increase in pro-inflammatory mediators. Parihar et al. (2018) found increased microglial activation after mice were irradiated with 5 and 30 cGy 4He particles. Chemokine CCL-3 was increased slightly after both 5 and 30 cGy. Zhou et al. (2017) irradiated juvenile rats with a single dose of 6 Gy nominal photon energy (4MV) and showed microglial proliferation in the external germinal layer of the cerebellum, while cytokines (IL-6, IL-18) and chemokines (CCL-2, GRO/KC) increased significantly. 

Essentiality 

In the absence of tissue-resident cell activation, an increase in pro-inflammatory mediators is not expected. The activation of tissue-resident cells can be attenuated by tamoxifen. Tamoxifen, an estrogen receptor modulator that can serve as a radiosensitizer, attenuated microglial activation and significantly decreased inflammatory cytokine production, including IL-1β and TNF-α, compared to the X-ray irradiated samples (4, 6, 8, 10 Gy) in absence of tamoxifen (Liu et al., 2010). A study by van Neerven et al. (2010) pretreated cells of mice cerebral cortices with a transcriptional activator, retinoic acid (RA) containing anti-inflammatory effects, for 12 h, and then exposed the cells for another 12 h to RA and LPS, an endotoxin which induces production of IL-1β, IL-6, TNFα in astrocytes. RA, when used with LPS, led to a significant reduction of the LPS-induced release of IL-1β, IL-6, TNF-α (van Neerven et al., 2010). Similarly, N-acetyl-L-cysteine (NAC) at 40 and 80 µM was able to reduce the LPS-induced levels of IL-6, TNF-α while preventing NF-κB nuclear translocation (Komatsu et al., 2017). NF-κB and AP-1 transcription factors binding to DNA indicate activated microglia, which was observed post-irradiation in the study by Ramanan et al. (2008). Radiation led to an increase in TNFα and IL-1β expression in microglia cultures, as well as an increase in Cox-2 protein levels. Treatment with SP 600125 (SP), a specific c-jun kinase inhibitor, which prevented AP-1 binding to DNA, was found to inhibit the radiation-induced increase in TNF-α, IL-1β, and Cox-2 expression. In contrast, treating BV-2 cells with 6-amino-4-(4-phenoxyphenylethylamino) quinazoline (Q), NF-κB activation inhibitor, prevented the increase in NF-κB binding to DNA, thus blocking the activation of tissue-resident cells, which then inhibited the radiation-induced increase in IL-1β expression but allowed the radiation-induced increases in Cox-2 and TNF-α. (Ramanan et al., 2008). Proinflammatory marker, ICAM-1, increased by 2.2-fold 72 h following 35 Gy irradiation (Kyrkanides et al. 2002). However, inhibition of Cox-2, a microglial activator, by NS-398 led to a 0.6-fold decrease in ICAM-1 levels induced by radiation in the brain (Kyrkanides et al. 2002). 

• More work could be done to observe this relationship in human models. 

• Limited data is available to support an understanding of this relationship at low doses (<0.1 Gy). 

Quantitative Understanding of the Linkage

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated. 

Dose Concordance 

Time Concordance 

Incidence Concordance 

It is well-characterized that activated tissue-resident cells can increase expression of pro-inflammatory mediators (Hladik & Tapio, 2016; Lumniczky, Szatmari & Safrany, 2017; Kaur et al., 2019). However, there exists a feedforward loop for this key event relationship as pro-inflammatory mediators can also activate tissue-resident cells within the brain and perpetuate the inflammatory response (Kim & Joh, 2006; Vezzani & Viviani, 2015). Thus, after stimulation by cytokines, chemokines or inflammogens such as from damaged neurons, microglia and astrocytes activate inflammatory signaling pathways, which result in increased expression and/or release of inflammatory mediators such as cytokines, eicosanoids, and metalloproteinases (Dong & Benveniste, 2001; Bourgognon & Cavanagh, 2020). Various studies have shown that overexpression of IL-1β in mouse models resulted in the appearance of inflammatory markers including activated glial cells and increased pro-inflammatory cytokine and chemokine mRNAs (Hein et al., 2010; Moore et al., 2009). Additionally, IL-6 plays a role in activating glial cells as mouse models with IL-6 knocked out showed reduced astrocytic population, as well as a reduced ability in activating microglia (Klein et al., 1997). Cytokines and chemokines can also increase the permeability of the blood-brain barrier, further increasing pro-inflammatory mediator levels (Lumniczky, Szatmari & Safrany, 2017). 

References

Betlazar, C. et al. (2016), "The impact of high and low dose ionising radiation on the central nervous system", Redox Biology, Vol. 9, Elsevier B.V., https://doi.org/10.1016/j.redox.2016.08.002. 

Bourgognon, J. M. and J. Cavanagh. (2020), "The role of cytokines in modulating learning and memory and brain plasticity", Brain and Neuroscience Advances, Vol. 4, SAGE Publications, https://doi.org/10.1177/2398212820979802. 

Boyd, A. et al. (2021), "Control of Neuroinflammation through Radiation-Induced Microglial Changes", Cells, Vol. 10/9, Multi-Disciplinary Digital Publishing Institute (MDPI), Basel,  https://doi.org/10.3390/cells10092381. 

Chen, H. et al. (2016), "Delayed activation of human microglial cells by high dose ionizing radiation", Brain Research, Vol. 1646, Elsevier B.V., https://doi.org/10.1016/j.brainres.2016.06.002. 

Chen, L. et al. (2018). “Inflammatory responses and inflammation-associated diseases in organs”, Oncotarget, Vol.9/6, Oncotarger, Orchard Park, https://doi.org/10.18632/oncotarget.23208 

Dheen, S. T., C. Kaur and E. Ling. (2007), "Microglial Activation and its Implications in the Brain Diseases", Current Medicinal Chemistry, Vol. 14/11, Bentham Science Publishers https://doi.org/10.2174/092986707780597961. 

Dong, Y. and E. N. Benveniste. (2001), "Immune function of astrocytes", Glia, Vol. 36/2, John Wiley & Sons, Hoboken, https://doi.org/10.1002/glia.1107. 

Dong, X. et al. (2015), "Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice", International Journal of Radiation Biology, Vol. 91/3, Informa Healthcare, London, https://doi.org/10.3109/09553002.2014.988895. 

Gray, J. I., & D. L. Farber (2022). “Tissue-Resident Immune Cells in Humans”, Annual Review of Immunology, Vol. 40/1, Annual Reviews, San Mateo, https://doi.org/10.1146/annurev-immunol-093019-112809 

Greene-Schloesser, D. et al. (2012), "Radiation-induced brain injury: A review", Frontiers in Oncology, Frontiers Media, Lausanne, https://doi.org/10.3389/fonc.2012.00073. 

Hein, A. M. et al. (2010), "Sustained hippocampal IL-1β overexpression impairs contextual and spatial memory in transgenic mice", Brain, Behavior, and Immunity, Vol. 24/2, https://doi.org/10.1016/j.bbi.2009.10.002. 

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research, Vol. 770, Elsevier B.V., https://doi.org/10.1016/j.mrrev.2016.08.003. 

Ivanova, E. A., & A. N. Orekhov. (2016), “Monocyte Activation in Immunopathology: Cellular Test for Development of Diagnostics and Therapy”, Journal of Immunology Research, Vol. 2016, Hindawi, https://doi.org/10.1155/2016/4789279 

Jeon, S. W. and Y. K. Kim. (2016), "Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?", World Journal of Psychiatry, Vol. 6/3, https://doi.org/10.5498/wjp.v6.i3.283. 

Jurga, A. M., M. Paleczna and K. Z. Kuter et al. (2020), "Overview of General and Discriminating Markers of Differential Microglia Phenotypes", Frontiers in Cellular Neuroscience, Vol. 14, Frontiers Media S.A., Lausanne, https://doi.org/10.3389/fncel.2020.00198. 

Kaur, D., V. Sharma and R. Deshmukh. (2019), "Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease", Inflammopharmacology, Vol. 27/4, Springer Nature, Berlin, https://doi.org/10.1007/s10787-019-00580-x. 

Kim, Y. S. and T. H. Joh. (2006), "Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease", Experimental & Molecular Medicine, Vol. 38/4, Springer Nature, Seoul, https://doi.org/10.1038/emm.2006.40. 

Klein, M. A. et al. (1997), "Impaired neuroglial activation in interleukin-6 deficient mice", Glia, Vol. 19/3, https://doi.org/10.1002/(SICI)1098-1136(199703)19:3<227::AID-GLIA5>3.0.CO;2-W. 

Komatsu, W. et al. (2017), “Nasunin inhibits the lipopolysaccharide-induced pro-inflammatory mediator production in RAW264 mouse macrophages by suppressing ROS-mediated activation of PI3 K/Akt/NF-κB and p38 signaling pathways”, Bioscience, Biotechnology, and Biochemistry, Vol. 81/10, Elsevier, https://doi.org/10.1080/09168451.2017.1362973 

Kyrkanides, S. et al. (2002), "Cyclooxygenase-2 modulates brain inflammation-related gene expression in central nervous system radiation injury", Molecular Brain Research, Vol. 104/2, Elsevier, https://doi.org/10.1016/S0169-328X(02)00353-4. 

Lee, W. H. et al. (2010), "Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain", International Journal of Radiation Biology, Vol. 86/2, Informa, London, https://doi.org/10.3109/09553000903419346. 

Liu, J. L. et al. (2010), "Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo", Brain Research, Vol. 1316, Elsevier B.V., https://doi.org/10.1016/j.brainres.2009.12.055. 

Lodermann, B. et al. (2012), “Low dose ionising radiation leads to a NF-κB dependent decreased secretion of active IL-1β by activated macrophages with a discontinuous dose-dependency”, International Journal of Radiation Biology, Vol. 88/10, Informa, London, https://doi.org/10.3109/09553002.2012.689464 

Lumniczky, K., T. Szatmári and G. Sáfrány. (2017), "Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain", Frontiers in Immunology, Vol. 8, Frontiers Media S.A., Lausanne, https://doi.org/10.3389/fimmu.2017.00517. 

Moore, A. H. et al. (2009), "Sustained expression of interleukin-1β in mouse hippocampus impairs spatial memory", Neuroscience, Vol. 164/4, https://doi.org/10.1016/j.neuroscience.2009.08.073. 

Parihar, V. K. et al. (2018), "Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice", Experimental Neurology, Vol. 305, Elsevier B.V., https://doi.org/10.1016/j.expneurol.2018.03.009. 

Patterson, S. L. (2015), "Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity", Neuropharmacology, Vol. 96, Elsevier B.V., https://doi.org/10.1016/j.neuropharm.2014.12.020. 

Phatnani, H. and T. Maniatis. (2015), "Astrocytes in Neurodegenerative Disease: Table 1.", Cold Spring Harbor Perspectives in Biology, Vol. 7/6, Cold Spring Harbor Laboratory Press, https://doi.org/10.1101/cshperspect.a020628. 

Ramanan, S. et al. (2008), "PPARα ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways", Free Radical Biology and Medicine, Vol. 45/12, Elsevier B.V., https://doi.org/10.1016/j.freeradbiomed.2008.09.002. 

Scharpfenecker, M. et al. (2012), “The TGF-β co-receptor endoglin regulates macrophage infiltration and cytokine production in the irradiated mouse kidney”, Radiotherapy and Oncology, Vol. 105/3, Elsevier B.V., https://doi.org/10.1016/J.RADONC.2012.08.021 

Smith, J. A. et al. (2012), "Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases", Brain Research Bulletin, Vol. 87/1, Elsevier B.V., https://doi.org/10.1016/j.brainresbull.2011.10.004. 

van Neerven, S. et al. (2010), "Inflammatory cytokine release of astrocytes in vitro is reduced by all-trans retinoic acid", Journal of Neuroimmunology, Vol. 229/1–2, Elsevier B.V., https://doi.org/10.1016/j.jneuroim.2010.08.005. 

Vezzani, A. and B. Viviani. (2015), "Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability", Neuropharmacology, Elsevier B.V.,  https://doi.org/10.1016/j.neuropharm.2014.10.027. 

Wang, Q. et al. (2020), "Radioprotective effect of flavonoids on ionizing radiation-induced brain damage", Molecules, MDPI AG, Basel, https://doi.org/10.3390/molecules25235719. 

Welser-Alves, J. V. and R. Milner. (2013), "Microglia are the major source of TNF-α and TGF-β1 in postnatal glial cultures; Regulation by cytokines, lipopolysaccharide, and vitronectin", Neurochemistry International, Vol. 63/1, Elsevier B.V., https://doi.org/10.1016/j.neuint.2013.04.007. 

Wu, Q. et al. (2017), “Macrophage biology plays a central role during ionizing radiation-elicited tumor response”, Biomedical Journal, Vol. 40/4, Elsevier, https://doi.org/10.1016/j.bj.2017.06.003 

Zhou, K. et al. (2017), "Radiation induces progenitor cell death, microglia activation, and blood-brain barrier damage in the juvenile rat cerebellum", Scientific Reports, Vol. 7, Springer Nature, London, https://doi.org/10.1038/srep46181. 

Relationship: 2835: Increase, Pro-Inflammatory Mediators leads to Abnormal Neural Remodeling

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Evidence for this relationship comes from rat and mouse models. There is in vivo evidence in both male and female animals, with more evidence in males. Animal age is occasionally not indicated in studies, but most evidence is in adult rodent models. 

Key Event Relationship Description

Inflammatory mediators such as IL-1β, TNF-α, and IL-6 can affect the normal behavior of neuronal cells through alterations in: (a) the neuronal architecture and (b) synaptic activity. Overexpression of these pro-inflammatory mediators can disrupt the integrity of neurons through increased necrosis and demyelination, decreased neurogenesis, neural stem cell proliferation and synaptic complexity (Cekanaviciute et al., 2018; Fan & Pang, 2017). Structurally, the neuron is comprised of the cell body, dendrites, axon, and axon terminals, all of which are critical in the normal functioning of the central nervous system. Another important component of the neuron is its signaling properties, which uses chemical neurotransmitters to transfer messages in the synaptic cleft (Cekanaviciute et al., 2018; Hladik & Tapio, 2016). Disruption to these structures or signaling properties results in abnormal neural remodeling.  

Under physiological conditions, cytokine levels are low, but these can increase in response to various insults. Cytokines mediate immune response through ligand binding to cell surface receptors, which activate signaling cascades such as the JAK-STAT or MAPK pathways to produce or recruit more cytokines. Once organs initiate inflammatory reactions, the cytokines are capable of impairing neural function through direct effects on neurons or by indirect mechanisms mediated by microglia, astrocytes or vascular endothelial cells (Mousa & Bakhiet, 2013; Prieto & Cotman, 2018).  

Evidence Supporting this KER

Overall Weight of Evidence: Moderate

Various studies provide support for the biological plausibility of the link between an increase in pro-inflammatory mediators and abnormal neural remodeling. It is known that cytokines and their receptors are constitutively expressed by neurons in the central nervous system, and even in normal or pathological states, these cytokines can be produced by individual cells and act on neurons. At the tissue level, the collective action and distribution of the cytokines can influence the overall inflammatory response within the brain tissue, impacting its function (Kishimoto et al., 1994).  One important factor in the pathogenesis of neurotoxicity is the overexpression of pro-inflammatory mediators, or Th1-type, cytokines. These cytokines bind to their receptors to induce a conformational change, which triggers the activation of intracellular signaling pathways that alter cell structure and function (Mousa and Bakhiet, 2013). Several sources have reported a change in physical and electrophysiological properties of neurons in either whole-brain samples, specific brain regions such as the hippocampus or dentate gyrus, or neuronal cell cultures in response to increased expression of cytokines (Jenrow et al., 2013; Fan and Pang, 2017; Wong et al., 2004). The main cytokines presenting detrimental effects are IL-1β, TNF-α, and IL-6, which can cause alterations in neuronal architecture such as morphological changes in dendrites and synapses (Tang et al., 2017; Cekanaviciute et al., 2018; Shi et al., 2017). Many studies have also reported decreased proliferation and differentiation in progenitor cells, inhibited neural stem cell differentiation and decreased neurogenesis following increases in cytokines (Zonis et al., 2015; Wong et al., 2004; Tang et al., 2017). IL-6 can affect neurogenesis through various distinct mechanisms. One mechanism is through the stimulation of hypothalamic-pituitary-adrenal axis, which then increases circulating glucocorticoids. These steroids can then inhibit cell proliferation and neurogenesis in the dentate gyrus (Turnbull and Rivier, 1999; Gould et al., 1992; Cameron and Gould, 1994). Decreased neurogenesis in the hippocampus is also well documented as a result of pro-inflammatory mediators, and one possible mechanism for this detrimental effect is through the interaction of IL-1β and orphan nuclear receptor, TLX. This receptor is required to maintain the neural precursor cell pool in neurogenic brain regions, and it has been shown that IL-1β can reduce the expression of TLX and consequently cell proliferation (Ryan et al., 2013). TNF-α affects neuronal fate by interacting with its receptor, TNFR1, which is expressed on neural stem cells. It has been reported that TNFR1-mediated signaling pathway inhibits growth therefore, a reduction in neuron production after TNF-α injection (Chen and Palmer, 2013). A clear mechanistic relationship has not yet been established, although it is accepted that pro-inflammatory mediators can alter the structure and function of neurons.

The empirical evidence collected for this KER comes from both in vitro and in vivo studies. Abnormal neural remodeling can be defined by changes to the physical, functional and/or electrophysiological properties of neurons. Most of the evidence examines effects of inflammation induced by either dextran sodium sulfate (DSS) treatment, seizure induction, heavy ion or X-ray irradiation at higher doses (>5 Gy) and varying dose-rates from 78.0 cGy/min to 3.2 Gy/min, or lipopolysaccharide injection on both in vivo and in vitro rodent models. Injections or treatments with pro-inflammatory cytokines were also used. These studies provide evidence to support a causal association between an increase in pro-inflammatory mediators and decreased neurogenesis, but also provide evidence of reduced neuronal signaling, neural stem cell and progenitor cell proliferation, as well as a change in overall neuronal shape (Zonis et al., 2015; Vallieres et al., 2002; Green et al., 2012; Wu et al., 2012; Chen and Palmer, 2013; Saraiva et al., 2019; Zhang et al., 2017; Dong et al., 2015; Kalm et al., 2013; Wong et al., 2004; Jenrow et al., 2013; Liu et al, 2010).  

Time Concordance 

Multiple studies suggest time-concordant relationship between increases in pro-inflammatory mediators leading to abnormal neural remodeling. The proliferation and survival of stem and progenitor cells, collectively known as neural precursor cells, was decreased or inhibited in response to increase pro-inflammatory cytokines at 4 days, 7 days and 1-month post-treatment (Zonis et al., 2015; Wong et al., 2004, Green et al., 2012; Ryan et al., 2013; Vallieres et al., 2002). Various studies also report a reduction in neurogenesis in the hippocampus and dentate gyrus 1-month post-treatment that was well-correlated with increased IL-1β, TNF-α, and IL-6 levels (Zonis et al., 2015; Vallieres et al., 2002; Wu et al., 2012; Chen and Palmer, 2013). In addition to a significant decrease in neurogenesis 1-month post-treatment, a study found that sustained IL-1β expression caused a significant reduction in neurogenesis that persisted for 3 months (Wu et al., 2012). Another study observed that X ray-induced increases in IL-1β and TNF-α at three and six hours resulted in a time-dependent decrease in DCX+ cells, a marker for neurogenesis, which persisted for 2 weeks. This was seen after a single dose of 10 Gy (Dong et al., 2015). Thus, these studies provide evidence to support time concordance of the relationship using both in vivo and in vitro models.  

Dose Concordance 

No available data. 

Incidence Concordance 

No available data. 

Essentiality 

Several treatments that directly alter pro-inflammatory mediators preserve neuronal integrity in the dentate gyrus and positively modulate hippocampal neurogenesis. The treatments included MW-151, a selective inhibitor of pro-inflammatory cytokine production and Kukoamine A, an alkaloid that inhibits neuronal oxidative stress and hippocampal apoptosis (Jenrow et al., 2013; Zhang et al., 2017). Another treatment used was histamine, which has been shown to ameliorate the loss of neuronal complexity and synaptic plasticity (Saraiva et al., 2019). Multiple studies use cytokine receptor antagonists or knock-out key receptors to block the effects of IL-1β, TNF-α, and CCL2, which have preserves neuron survival (Green et al., 2012; Ryan et al., 2013; Wu et al., 2012; Chen and Palmer, 2013). Another knockout model of complement component 3 (C3) have also been used to demonstrate essentiality. C3 is a central molecule in the complement cascade, and its roles include microglia-mediated synapse elimination. C3 knockout models have been shown to cause reduced pro-inflammatory cytokines, increased synaptic number, reduced neuron loss and synaptic morphology impairment (Shi et al., 2017). 

• Various in vitro studies have reported a stimulation of neural precursor cell proliferation and differentiation or increased neurogenesis by different cytokines such as IL-6 and IFN-γ (Islam et al., 2009; Wong et al., 2004). Another study found increased proliferation within the hippocampus after repeated IL-6 and IL-1β infusion (Seguin et al., 2009). Although a clear mechanism has not yet been elucidated, it is thought that these cytokines have contradictory effects from the differential activation of various signaling cascades (Borsini et al., 2015). For example, hyper-IL-6, a fusion of IL-6 and IL-6 receptor, was found to increase neurogenesis through the activation of MAPK/CREB (mitogen-activated protein kinase/cAMP response element binding protein) cascade (Islam et al., 2009). 
• It has also been reported that TNF-α exhibits neuroprotective effects as their transmembrane receptors can influence different signaling pathways (Figiel, 2008; Masli & Turpie, 2009)

• Kalm et al. (2013) found a higher inflammatory response in lipopolysaccharide (LPS) treated females compared with males after irradiation. Specifically, increased levels of pro-inflammatory cytokines IL-1β, IL-12, and IL-17, as well as pro-inflammatory chemokines CCL4, CCL3 and CCL2 were detected relative to vehicle-treated animals and LPS-treated males. This was associated with a 32% decrease in DCX+ cells, a marker for neurogenesis, in females. However, in LPS-treated males, a 64% reduction in DCX+ cells compared to vehicle-treated males following irradiation was reported (Kalm et al., 2013). Further research is required to elucidate the exact effects of increased pro-inflammatory mediators on neural integrity between males and females. 

Quantitative Understanding of the Linkage

The table below provides some representative examples of quantitative linkages between the two key events as presented in the paper. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated. 

Time Concordance 

NA

References

Borsini, A. et al. (2015), "The role of inflammatory cytokines as key modulators of neurogenesis", Trends in Neurosciences, Vol. 38/3, Elsevier, Amsterdam, https://doi.org/10.1016/j.tins.2014.12.006. 

Cameron, H. A. and E. Gould. (1994), "Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus", Neuroscience, Vol. 61/2, Elsevier, Amsterdam, https://doi.org/10.1016/0306-4522(94)90224-0. 

Cekanaviciute, E., S. Rosi and S. V. Costes. (2018), "Central nervous system responses to simulated galactic cosmic rays", International Journal of Molecular Sciences, Vol. 19/11, Multi-Disciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms19113669. 

Chen, Z. and T. D. Palmer. (2013), "Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis", Brain, Behavior, and Immunity, Vol. 30, Elsevier Inc., Amsterdam, https://doi.org/10.1016/j.bbi.2013.01.083. 

Dong, X. et al. (2015), "Relationship between irradiation-induced neuro-inflammatory environments and impaired cognitive function in the developing brain of mice", International Journal of Radiation Biology, Vol. 91/3, Taylor & Francis Group, London, https://doi.org/10.3109/09553002.2014.988895. 

Fan, L. W. and Y. Pang. (2017), "Dysregulation of neurogenesis by neuroinflammation: Key differences in neurodevelopmental and neurological disorders", Neural Regeneration Research, Vol. 12/3, Wolters Kluwer, Alphen aan den Rijn, https://doi.org/10.4103/1673-5374.202926. 

Figiel, I. (2008) “Pro-inflammatory cytokine TNF-alpha as a neuroprotective agent in the brain.” Acta neurobiologiae experimentalis,Vol. 68/4, Nencki Institute of Experimental Biology, Warsaw, 526-34, https://doi.org/10.55782/ane-2008-1720 

Gould, E. et al. (1992), "Adrenal hormones suppress cell division in the adult rat dentate gyrus", The Journal of Neuroscience, Vol. 12/9, Society for Neuroscience, Washington, https://doi.org/10.1523/JNEUROSCI.12-09-03642.1992. 

Green, H. F. et al. (2012), "A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells", Molecular and Cellular Neuroscience, Vol. 49/3, Elsevier Inc., Amsterdam, https://doi.org/10.1016/j.mcn.2012.01.001. 

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research - Reviews in Mutation Research, Vol. 770, Elsevier B.V., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.003. 

Hunsberger, H. C. et al. (2019), "The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions", Neuronal Signaling, Vol. 3/2, Portland Press, London, https://doi.org/10.1042/NS20180203. 

Islam, O. et al. (2009), "Interleukin-6 and Neural Stem Cells: More Than Gliogenesis", (C.-H. Heldin, Ed.)Molecular Biology of the Cell, Vol. 20/1, The American Society for Cell Biology, Rockville, https://doi.org/10.1091/mbc.e08-05-0463. 

Jenrow, K. A. et al. (2013), "Selective Inhibition of Microglia-Mediated Neuroinflammation Mitigates Radiation-Induced Cognitive Impairment", Radiation Research, Vol. 179/5, Bio One, Washington, https://doi.org/10.1667/RR3026.1. 

Kalm, M., K. Roughton and K. Blomgren. (2013), "Lipopolysaccharide sensitized male and female juvenile brains to ionizing radiation", Cell Death & Disease, Vol. 4/12, https://doi.org/10.1038/cddis.2013.482. 

Kishimoto, T., T. Taga and S. Akira. (1994), "Cytokine signal transduction", Cell, Vol. 76/2, Elsevier, Amsterdam, https://doi.org/10.1016/0092-8674(94)90333-6. 

Liu, J.-L. et al. (2010), "Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo", Brain Research, Vol. 1316, Elsevier, Amsterdam, https://doi.org/10.1016/j.brainres.2009.12.055. 

Masli, S, and B. Turpie. (2009) “Anti-inflammatory effects of tumour necrosis factor (TNF)-alpha are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-beta-treated antigen-presenting cells.” Immunology, Vol. 127/1 (2009), John Wiley & Sons, Inc., Hoboken, https://doi.org/10.1111/j.1365-2567.2008.02933.x 

Mousa, A. and M. Bakhiet. (2013), "Role of Cytokine Signaling during Nervous System Development", International Journal of Molecular Sciences, Vol. 14/7, Multi-Disciplinary Digital Publishing Institute, Basel, https://doi.org/10.3390/ijms140713931. 

Prieto, G. A. and C. W. Cotman. (2017), "Cytokines and cytokine networks target neurons to modulate long-term potentiation", Cytokine & Growth Factor Reviews, Vol. 34, Elsevier, Amsterdam, https://doi.org/10.1016/j.cytogfr.2017.03.005. 

Ryan, S. M. et al. (2013), "Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation", Brain, Behavior, and Immunity, Vol. 33, Elsevier, Amsterdam, https://doi.org/10.1016/j.bbi.2013.03.005. 

Saraiva, C. et al. (2019), "Histamine modulates hippocampal inflammation and neurogenesis in adult mice", Scientific Reports, Vol. 9/1, Springer Nature, Berlin, https://doi.org/10.1038/s41598-019-44816-w. 

Seguin, J. A. et al. (2009), "Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration.", Neuropsychiatric disease and treatment, Vol. 5, Dove Press Ltd., Macclesfield, http://www.ncbi.nlm.nih.gov/pubmed/19557094. 

Shi, Q. et al. (2017), "Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice", Science Translational Medicine, Vol. 9/392, American Association for the Advancement of Science, Washington, https://doi.org/10.1126/scitranslmed.aaf6295. 

Tang, F. R., W. K. Loke and B. C. Khoo. (2017), "Postnatal irradiation-induced hippocampal neuropathology, cognitive impairment and aging", Brain and Development, Vol. 39/4, Elsevier, Amsterdam, https://doi.org/10.1016/j.braindev.2016.11.001. 

Turnbull, A. V. and C. L. Rivier. (1999), "Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action", Physiological Reviews, Vol. 79/1, American Physiology Society, Rockville, https://doi.org/10.1152/physrev.1999.79.1.1. 

Valliéres, L. et al. (2002), "Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6", Journal of Neuroscience, Vol. 22/2, Society for Neuroscience, Washington, https://doi.org/10.1523/jneurosci.22-02-00486.2002. 

Wong, G., Y. Goldshmit and A. M. Turnley. (2004), "Interferon-γ but not TNFα promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells", Experimental Neurology, Vol. 187/1, Elsevier, Amsterdam, https://doi.org/10.1016/j.expneurol.2004.01.009. 

Wu, M. D. et al. (2012), "Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running", Brain, Behavior, and Immunity, Vol. 26/2, Elsevier Inc., Amsterdam, https://doi.org/10.1016/j.bbi.2011.09.012. 

Zhang, Y. et al. (2017), "Kukoamine A Prevents Radiation-Induced Neuroinflammation and Preserves Hippocampal Neurogenesis in Rats by Inhibiting Activation of NF-κB and AP-1", Neurotoxicity Research, Vol. 31/2, Springer Nature, Berlin, https://doi.org/10.1007/s12640-016-9679-4. 

Zhu, Y. et al. (2012), "APOE genotype alters glial activation and loss of synaptic markers in mice", Glia, Vol. 60/4, John Wiley & Sons, Inc., Hoboken, https://doi.org/10.1002/glia.22289. 

Zonis, S. et al. (2015), "Chronic intestinal inflammation alters hippocampal neurogenesis", Journal of Neuroinflammation, Vol. 12/1, Springer Nature, Berlin, https://doi.org/10.1186/s12974-015-0281-0. 

Relationship: 2836: Abnormal Neural Remodeling leads to Impairment, Learning and memory

AOPs Referencing Relationship

Evidence Supporting Applicability of this Relationship

Evidence for this relationship comes from rat and mouse models. There is in vivo evidence in both male and female animals, with more evidence in males. Animal age is occasionally not indicated in studies, but most evidence is in adult rodent models. 

Key Event Relationship Description

Neural stem cells (NSCs) come from different sources, such as the subgranular zone (SGZ) located in the dentate gyrus (DG) of the hippocampal formation, and the subventricular zone (SVZ) region of the brain. NSCs give rise to mature neurons that are then able to receive signals from other neurons (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016; Monje & Palmer, 2003; Romanella et al., 2020; Tomé et al., 2015). Changes in neuronal architecture can lead to altered synaptic activity, necrosis, demyelination, neurogenesis, neurodegeneration, and dendrite morphology, all of which encompass abnormal neural remodeling (Hladik & Tapio, 2016; Monje & Palmer, 2003; Tomé et al., 2015). These alterations can then cause cognitive deficits in the form of impaired learning and memory (Barker & Warburton, 2011; Hladik & Tapio, 2016; Monje & Palmer, 2003; Tomé et al., 2015). Impaired learning consists reduced ability to create new associative or non-associative relationships, whereas impaired memory consists of decreased ability to establish sensory, short-term or long-term memories (Desai et al., 2022; Kiffer et al., 2019). Multiple brain areas are involved these processes, such as the hippocampal region, amygdala, prefrontal cortex, basal ganglia, and other areas of the neocortex (Cucinotta et al., 2014; Desai et al., 2022; NCRP Commentary, 2016). 

Evidence Supporting this KER

Overall Weight of Evidence: Moderate

Several reviews provide support for the biological plausibility of the link between abnormal neural remodeling and impaired learning and memory. It is generally accepted that abnormal neural remodeling can disrupt learning and memory through changes to neurogenesis, neurodegeneration, neuronal excitability and synaptic plasticity, demyelination and dendritic spine density (Hladik & Tapio, 2016; Bálentová & Adamkov, 2020; Tomé et al., 2015; Monje & Palmer, 2003; Romanella et al., 2020). 

Neurogenesis in the DG creates new neurons in the hippocampus that can make connections to Cornu Ammonis (CA) neurons involved in learning and memory (Monje & Palmer, 2003; Tomé et al., 2015). Accordingly, learning and memory can be impaired through reduced neurogenesis in the neurogenic SGZ of the DG (Bálentová & Adamkov, 2020; Monje & Palmer, 2003). Many studies also associate decreased neurogenesis to impaired hippocampal-dependent cognitive function, indicating that it is a common mechanism for the relationship (Tomé et al., 2015). Similarly, apoptosis and neurodegeneration impair cognitive function (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016). In the hippocampus, the degree of atrophy corresponds to the degree of impaired learning and memory (Tomé et al., 2015).  

Synaptic strength and neuronal excitability are important components of learning and memory. Decreased hippocampal excitability and disrupted long-term potentiation (LTP), a form of long-term synaptic plasticity, are associated with reduced learning and memory (Romanella et al., 2020). Changes in the expression of synaptic receptors and other synaptic proteins may also result in impaired learning and memory (Hladik & Tapio, 2016). 

Demyelination correlates with decreased long-term memory formation (Tomé et al., 2015) and along with white matter necrosis, these lead to impaired learning and memory (Bálentová & Adamkov, 2020). Although demyelination is a factor in learning and memory, sub-threshold demyelination may still cause impaired learning and memory (Monje & Palmer, 2003). 

Reduced dendritic complexity and spine density are also associated with impaired learning and memory (Bálentová & Adamkov, 2020; Hladik & Tapio, 2016; Romanella et al., 2020). The complexity of signal processing in the hippocampus can be reduced by a loss in dendritic spines, which results in impaired learning and memory (Romanella et al., 2020). In addition, various studies show reduced dendritic branching, length and area in hippocampal neurons associated with learning and memory (Hladik & Tapio, 2016). 

The empirical evidence surrounding this KER stems from research using in vivo models. When compared to the control, irradiated subjects demonstrated significant changes in neuronal integrity and cognitive deficits (Achanta, Fuss & Martinez, 2009; Acharya et al., 2019; Akiyama et al., 2001; Hodges et al., 1998; Howe et al., 2019; Krukowski et al., 2018; Madsen et al., 2003; Miry et al., 2021; Parihar et al., 2015, 2016; Raber et al., 2004; Rola et al., 2004; Simmons et al., 2019; Sorokina et al., 2021; Whoolery et al., 2017; Winocur et al., 2006). 

Dose Concordance 

There is strong evidence suggesting dose-concordance between abnormal neural remodeling and impaired learning and memory. Dose-dependent changes in dendritic complexity are correlated with behavioral deficits at doses from 0.05 to 30 Gy (Bálentová & Adamkov, 2020; Howe et al., 2019; Parihar et al., 2015, 2016; Simmons et al., 2019; Whoolery et al., 2017). Mice exposed to 0.05 and 0.3 Gy of 48Ti showed dose-dependent decreases in total dendritic length and number of dendritic branch points. When subjected to cognitive testing, mice exposed to 0.3 Gy demonstrated greater impairment in the novel object recognition (NOR) and object in place (OiP) tests compared to 0.05 Gy exposed mice (Parihar et al., 2016). These results for OiP were correlated positively to the number of dendritic spines and negatively to the number of postsynaptic density protein 95, also a marker for abnormal neural remodeling. Similarly, another study identified a correlation between the total number of dendritic spines and the performance of mice in the OiP task (Parihar et al., 2015). This study also demonstrated dose-dependent decreases in the total number of spines, total dendritic length, number of branch points, number of dendritic branches, and DI in both the NOR and OiP tasks when exposed to 0.05 and 0.3 Gy of 16O and 48Ti. 

Changes in the levels of neurogenesis also exhibit dose-concordance with cognitive deficits. Whoolery et al. (2017) identified a 0.8- and 0.4-fold decrease in the number of Ki-67+ cells in male mice exposed to 0.2 and 1 Gy of 28Si particles, respectively. The mice also demonstrated a decrease in percentage freezing by 0.4-fold in contextual FC, indicative of impaired learning and memory, when exposed to 0.2 Gy, although no significant changes in learning and memory were seen at 1 Gy. Another study identified dose-dependent decreases in the numbers of Ki67+ and BrdU+ cells in three age groups (postnatal day (PD) 21, PD 50, and PD 70) in rats exposed to 0.3, 3, and 10 Gy of ionizing radiation (Achanta, Fuss & Martinez, 2009). In PD 21 rats, dose-dependent decreases in freezing response were observed at doses of 0.3 and 10 Gy during the trace fear conditioning/testing. These results show that higher doses of irradiation lead to greater alterations in neuronal integrity, correlated with greater cognitive impairments. Many other studies showed decreased neurogenesis or increased neurodegeneration and impaired learning and memory at doses from 0.3 to 25 Gy, with stressors like X-rays, gamma rays, carbon ions and iron ions (Achanta, Fuss & Martinez, 2009; Akiyama et al., 2001; Hodges et al., 1998; Madsen et al., 2003; Miry et al., 2021; Raber et al., 2004; Rola et al., 2004; Sorokina et al., 2021; Winocur et al., 2006). 

Neuron excitation has also been measured to assess neuron integrity. After 0.18 Gy of 252Cf neutron, with an activity of 1.6 GBq, excitatory signaling in CA1 neurons of mice was reduced and both NOR and OiP showed decreased learning and memory (Acharya et al., 2019). 

Synaptic composition in hippocampal neurons was assessed as well to determine neuron integrity. GluR1, involved in hippocampal-dependent working memory, and recognition memory were both reduced after 0.5 Gy of simulated galactic cosmic radiation (GCR) (Krukowski et al., 2018). 

Time Concordance 

Evidence supporting time concordance between abnormal neural remodeling and impaired learning and memory come from several studies. Whoolery et al. (2017) found that the number of Ki-67+ cells decreased 24 hours after 0.2 Gy of 28Si radiation of mice, while contextual FC 3 months after radiation showed impaired memory. Similarly, after 10 Gy X-rays, cell proliferation and the number of immature neurons decreased by 95% in mice after 3 months, and a Barnes maze showed impaired hippocampal-dependent spatial learning and memory measured after proliferation at 3 months as well (Raber et al., 2004). After mice were irradiated with 16O and 48Ti particles at 0.05 and 0.30 Gy, dendritic complexity and spine density were reduced and synaptic spine puncta were increased 15 weeks post-irradiation while learning and memory was impaired 15 and 24 weeks post-irradiation (Parihar et al., 2016). Neurogenesis was reduced immediately after 3 Gy 300 kVp X-ray radiation in rats and remained low 2 and 6 weeks later, and memory was impaired 1, 3 and non-significantly at 7 weeks post-irradiation (Madsen et al., 2003). Rats irradiated with gamma rays showed decreased neurogenesis and impaired performance during FC both 4 weeks post-irradiation (Winocur et al., 2006). In a longer-term study, neurogenesis was impaired 1 and 3 months after 5 Gy X-ray radiation in mice, while the Morris Water Maze (MWM) demonstrated impaired learning and memory also at 3 months (Rola et al., 2004). This trend continued after 9 months where both learning and memory through NOR testing and abnormal neural remodeling through mushroom and thin spine density were reduced after mice were irradiated with 0.05 Gy 16O particles (Howe et al., 2019). Hodges et al. (1998) showed abnormal neural remodeling at 41 weeks after 250 kVp X-ray irradiation and impaired learning and memory from 35 to 44 weeks post-irradiation.

Incidence Concordance 

No available data.  

Essentiality 

No identified studies applied countermeasures to support the causal relationship between abnormal neural remodeling and impaired learning and memory.

• One study observed cognitive deficits in the one- and two-way avoidance, press-lever avoidance, and water maze tests, but through pathological examination, no abnormalities were seen in the brains (white matter and axons were normal with no inflammation or glial response) (Lamproglou et al., 1995). This is indicative of impaired cognition without any changes in neuron integrity.  

• At 25 Gy of X-irradiation, Hodges et al. (1998) observed both abnormal neural remodeling and impaired learning and memory. However, at 20 Gy in the same study, abnormal neural remodeling was not observed.

• Whoolery et al. (2017) found that abnormal neural remodeling was high at 1 Gy and low and 0.2 Gy but found impaired learning and memory at 0.2 Gy and not at 1 Gy.  

• Miry et al. (2021) found that 1 Gy of 56Fe particles led to increased learning and memory 20 months after exposure, although this is part of the compensatory or repair mechanisms following early suppressive changes.  

Quantitative Understanding of the Linkage

The table below provides some representative examples of quantitative linkages between the two key events. It was difficult to identify a general trend across all the studies due to differences in experimental design and reporting of the data. All data is statistically significant unless otherwise stated. 

Dose Concordance 

Time Concordance 

NA

References

Achanta, P., M. Fuss and J. L. Martinez. (2009), "Ionizing Radiation Impairs the Formation of Trace Fear Memories and Reduces Hippocampal Neurogenesis", Behavioral Neuroscience, Vol. 123/5, https://doi.org/10.1037/a0016870. 

Acharya, M. M. et al. (2019), "New concerns for neurocognitive function during deep space exposures to chronic, low dose-rate, neutron radiation", eNeuro, Vol. 6/4, Society for Neuroscience, https://doi.org/10.1523/ENEURO.0094-19.2019. 

Akiyama, K. et al. (2001), "Cognitive Dysfunction and Histological Findings in Adult Rats One Year After Whole Brain Irradiation.", Neurologia medico-chirurgica, Vol. 41/12, Japan Neurological Society, https://doi.org/10.2176/nmc.41.590. 

Bálentová, S. and M. Adamkov. (2020), "Pathological changes in the central nervous system following exposure to ionizing radiation", Physiological Research, Czech Academy of Sciences, https://doi.org/10.33549/PHYSIOLRES.934309. 

Burgess, N. (2002), "The hippocampus, space, and viewpoints in episodic memory", The Quarterly Journal of Experimental Psychology, Vol. 55/4, Experimental Psychology Society, https://doi.org/10.1080/02724980244000224. 

Cucinotta, F. A. et al. (2014), "Space radiation risks to the central nervous system", Life Sciences in Space Research, Vol. 2, Elsevier Ltd, Amsterdam, https://doi.org/10.1016/j.lssr.2014.06.003. 

Desai, R. I. et al. (2022), "Impact of spaceflight stressors on behavior and cognition: A molecular, neurochemical, and neurobiological perspective", Neuroscience & Biobehavioral Reviews, Vol. 138, Elsevier, Amsterdam, https://doi.org/10.1016/j.neubiorev.2022.104676. 

D’Hooge, R. and P. P. De Deyn. (2001), "Applications of the Morris water maze in the study of learning and memory", Brain Research Reviews, Vol. 36/1, Elsevier B.V., https://doi.org/10.1016/S0165-0173(01)00067-4. 

Hladik, D. and S. Tapio. (2016), "Effects of ionizing radiation on the mammalian brain", Mutation Research - Reviews in Mutation Research, Vol. 770, Elsevier B.V., https://doi.org/10.1016/j.mrrev.2016.08.003. 

Hodges, H. et al. (1998), "Late behavioural and neuropathological effects of local brain irradiation in the rat", Behavioural Brain Research, Vol. 91/1–2, Elsevier, https://doi.org/10.1016/S0166-4328(97)00108-3. 

Howe, A. et al. (2019), "Long-term changes in cognition and physiology after low-dose 16 O irradiation", International Journal of Molecular Sciences, Vol. 20/1, MDPI AG, https://doi.org/10.3390/ijms20010188. 

Kiffer, F., M. Boerma and A. Allen. (2019b), "Behavioral effects of space radiation: A comprehensive review of animal studies", Life Sciences in Space Research, Vol. 21, Elsevier, Amsterdam, https://doi.org/10.1016/j.lssr.2019.02.004. 

Krukowski, K. et al. (2018), "Female mice are protected from space radiation-induced maladaptive responses", Brain, Behavior, and Immunity, Vol. 74, Academic Press Inc., https://doi.org/10.1016/j.bbi.2018.08.008. 

Lamproglou, I. et al. (1995), "Radiation-induced cognitive dysfunction: An experimental model in the old rat", International Journal of Radiation Oncology, Biology, Physics, Vol. 31/1, Elsevier, https://doi.org/10.1016/0360-3016(94)00332-F. 

Madsen, T. M. et al. (2003), "Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat", Neuroscience, Vol. 119/3, Elsevier Ltd, https://doi.org/10.1016/S0306-4522(03)00199-4. 

Miry, O. et al. (2021), "Life-long brain compensatory responses to galactic cosmic radiation exposure", Scientific Reports 2021 11:1, Vol. 11/1, Nature Publishing Group, https://doi.org/10.1038/s41598-021-83447-y. 

Monje, M. L. and T. Palmer. (2003), "Radiation injury and neurogenesis", Current Opinion in Neurology, Vol. 16/2, Ovid Technologies (Wolters Kluwer Health), https://doi.org/10.1097/01.wco.0000063772.81810.b7. 

National Council on Radiation Protection and Measures (NCRP). (2016). Commentary No. 25 – Potential for central nervous system effects from radiation exposure during space activities phase I: Overview.   

Parihar, V. K. et al. (2016), "Cosmic radiation exposure and persistent cognitive dysfunction", Scientific Reports, Vol. 6/1, Nature Publishing Group, https://doi.org/10.1038/srep34774. 

Parihar, V. K. et al. (2015), "What happens to your brain on the way to Mars", Science Advances, Vol. 1/4, American Association for the Advancement of Science, https://doi.org/10.1126/SCIADV.1400256. 

Raber, J. et al. (2004), "Radiation-induced cognitive impairments are associated with changes in indicators of hippocampal neurogenesis", Radiation Research, Vol. 162/1, Allen Press, https://doi.org/10.1667/RR3206. 

Rola, R. et al. (2004), "Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice", Experimental Neurology, Vol. 188/2, Academic Press Inc., https://doi.org/10.1016/j.expneurol.2004.05.005. 

Romanella, S. M. et al. (2020), "Noninvasive Brain Stimulation &amp; Space Exploration: Opportunities and Challenges", Neuroscience & Biobehavioral Reviews, Vol. 119, https://doi.org/10.1016/j.neubiorev.2020.09.005. 

Simmons, D. A. et al. (2019), "Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation", Radiotherapy and Oncology, Vol. 139, https://doi.org/10.1016/j.radonc.2019.06.006. 

Sorokina, S. S. et al. (2021), "Low dose of carbon ion irradiation induces early delayed cognitive impairments in mice", Radiation and Environmental Biophysics, Vol. 60, Nature, https://doi.org/10.1007/s00411-020-00889-0. 

Tomé, W. A. et al. (2015), "Hippocampal-dependent neurocognitive impairment following cranial irradiation observed in pre-clinical models: current knowledge and possible future directions", The British Journal of Radiobiology, Vol. 89/1057, British Institute of Radiology, https://doi.org/10.1259/bjr.20150762. 

Vorhees, C. V. and M. T. Williams. (2014), "Assessing Spatial Learning and Memory in Rodents", ILAR Journal, Vol. 55/2, Oxford University Press, Oxford, https://doi.org/10.1093/ilar/ilu013. 

Whoolery, C. W. et al. (2017), "Whole-body exposure to 28Si-radiation dose-dependently disrupts dentate gyrus neurogenesis and proliferation in the short term and new neuron survival and contextual fear conditioning in the long term", Radiation Research, Vol. 188/5, Radiation Research Society, https://doi.org/10.1667/RR14797.1. 

Winocur, G. et al. (2006), "Inhibition of neurogenesis interferes with hippocampus-dependent memory function", Hippocampus, Vol. 16/3, https://doi.org/10.1002/HIPO.20163.

Relationship: 3321: Altered Stress Response Signaling leads to Abnormal Neural Remodeling