This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 3315

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, DNA strand breaks leads to Altered Stress Response Signaling

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, DNA strand breaks

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Altered Stress Response Signaling

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Deposition of energy leads to abnormal vascular remodeling	adjacent	High	Moderate	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed
Deposition of Energy Leading to Learning and Memory Impairment	adjacent	Moderate	Low	Vinita Chauhan (send email)	Open for citation & comment	WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens	Low	NCBI
mouse	Mus musculus	Moderate	NCBI
rat	Rattus norvegicus	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Male	Moderate
Female	Low

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
Juvenile	Low
Adult	Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

DNA strand breaks can lead to altered signaling of various pathways through the DNA damage response. DNA strand breaks, which are a form of DNA damage, can induce ataxia telangiectasia mutated (ATM) and ATM/RAD3-related (ATR), two phosphoinositide 3-kinase (PI3K)-related serine/threonine kinases (PIKKs) (Abner and McKinnon, 2004; Lee and McKinnon, 2007; Nagane et al., 2021; Sylvester et al., 2018; Thadathil et al., 2019; Wang et al., 2020; Wang et al., 2017). Following DNA strand breaks, cellular DNA damage response signaling can phosphorylate downstream proteins and activate several transcription factors and pathways (Wang et al., 2017). Spontaneous DNA strand breaks from endogenous sources will induce signaling as a normal response to facilitate DNA repair. However, excessive DNA damage induced by a stressor will result in increased activation of these pathways and subsequent harmful downstream effects. Stress response signaling pathways induced by DNA strand breaks include p53/p21 (Abner and McKinnon, 2004; Baselet et al., 2018; Lee and McKinnon, 2007; Nagane et al., 2021; Sylvester et al., 2018; Thadathil et al., 2019; Wang et al., 2020; Wang et al., 2017), caspase (Abner and McKinnon, 2004; Baselet et al., 2019; Wang et al., 2020; Wang et al., 2016) and mitogen-activated protein kinase (MAPK) family pathways (Ghahremani et al., 2002; Nagane et al., 2021).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Overall weight of evidence: Moderate

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

There is strong evidence supporting the link between DNA strand breaks leading to altered stress response signaling. Single strand breaks (SSBs) or double strand breaks (DSBs) in DNA from both endogenous and exogenous sources can induce the DNA damage response, which can result in the induction of various signaling pathways (Baselet et al., 2019). DNA strand breaks are well known to lead to the activation of ATM and ATR as part of the normal DNA damage response (Abner and McKinnon, 2004; Baselet et al., 2019; Lee and McKinnon, 2007; Nagane et al., 2021; Sylvester et al., 2018; Thadathil et al., 2019; Wang et al., 2020; Wang et al., 2017; Wang et al., 2016). While ATM tends to be recruited to DSBs, ATR is recruited by many types of DNA damage including both DSBs and SSBs (Maréchal and Zou, 2013; Wang et al., 2017). Following a DNA DSB, the Mre11-Rad50-Nbs1 (MRN) complex senses and directly binds to the DNA ends at the site of the break, which subsequently activates ATM (Lee and McKinnon, 2007; Maréchal and Zou, 2013). Following a DNA SSB, resection of the damaged strand by apurinic/apyrimidinic endonuclease (APE)1/APE2 is followed by coating the single-stranded DNA with replication protein A (RPA), where the recruitment of the ATR- ATR interacting protein (ATRIP) complex and the activation of ATR occurs (Caldecott, 2022; Maréchal and Zou, 2013).

ATM and ATR can phosphorylate over 700 proteins (Nagane et al., 2021), and phosphorylation of key signaling proteins by ATM/ATR will alter signaling in their respective pathways. High levels of DNA strand breaks induced by exogenous stressors will enhance ATM/ATR activation and subsequently further activate downstream signaling, leading to downstream consequences. The extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK subfamily pathways can be phosphorylated and activated by ATM/ATR (Ghahremani et al., 2002; Nagane et al., 2021). Additionally, ATM/ATR can phosphorylate p53 on serine 15 to enhance the stability of p53, leading to activation of the p53 pathway and changes in the transcriptional activity of p53 (Abner and McKinnon, 2004; Baselet et al., 2019; Lee and McKinnon, 2007; Nagane et al., 2021; Sylvester et al., 2018; Thadathil et al., 2019; Wang et al., 2020; Wang et al., 2017; Wang et al., 2016). The apoptosis pathway downstream of p53 can also be activated by DNA strand breaks (Abner and McKinnon, 2004; Baselet et al., 2019; Lee and McKinnon, 2007; Thadathil et al., 2019; Wang et al., 2020).

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Evidence for this relationship was collected from studies using in vivo models of mice and rats as well as in vitro models of cells derived from human, mice or rats. The stressors used to support this relationship include 137Cs gamma rays and X rays. Markers of DNA strand breaks in this KER include p53 binding protein 1 (53BP1), phosphorylation of H2AX (γ-H2AX), phosphorylation of ATR (p-ATR) and phosphorylation of ATM (p-ATM). Altered signaling was measured mostly by the protein expression of the p53/p21 and apoptosis pathways.

Dose Concordance

A few studies have indicated a dose concordance between the increase in DNA strand breaks and altered stress response signaling. X-ray irradiation of rat cortical neurons showed increased DNA damage markers, γ-H2AX, p-ATM and p-ATR and increased levels of signaling proteins, including p21, p-p53 and cleaved caspase 3 at both doses of 8 and 32 Gy (Sabirzhanov et al., 2020). 137Cs gamma irradiated cerebromicrovascular endothelial cells (CMVECs) and rat hippocampal neurons showed increased DNA strand breaks, measured by comet assay, at 2-10 Gy, and increased caspase 3/7 activity at 2, 4 and 6 Gy (Ungvari et al., 2013).

Time Concordance

Many studies demonstrate that DNA strand breaks occur before altered signaling in a time course. Although both KEs can occur quickly, Gionchiglia et al. (2021) showed in mice that γ-H2AX and p53BP1 foci were increased as early as 15 minutes after 10 Gy of X-ray irradiation while cleaved caspase 3 did not increase until 30 minutes after irradiation. In HT22 hippocampal neurons irradiated with 12 Gy of X-rays, γ-H2AX and p-ATM were increased at 30 minutes post-irradiation while p53 was increased after 1 h and caspase 3 was increased after 48 h (Zhang et al., 2017). Similarly, rat cortical neurons irradiated with 8 Gy of X-rays showed increased p-ATM, γ-H2AX and p-ATR after 30 minutes, while p-p53, p21 and cleaved caspase 3 did not increase until 3 or 6 h post-irradiation (Sabirzhanov et al., 2020). Multiple studies using human- and rat-derived endothelial cells irradiated with 4 Gy of 137Cs gamma rays show increased DNA strand breaks at 1 h post-irradiation, with altered signaling to p53 and p21 at 6 h and to caspase 3/7 at 18 h post-irradiation (Kim et al., 2014; Park et al., 2022; Ungvari et al., 2013). In a longer-term study irradiating human lung microvascular endothelial cells (HMVEC-L) with 15 Gy of X-rays, increased DNA strand breaks were observed at 14 days post-irradiation, while altered signaling in the p53 pathway was observed at 21 days post-irradiation (Lafargue et al., 2017).

Incidence concordance

A few studies have demonstrated an incidence concordance between DNA strand breaks and altered signaling at equivalent doses. Following X-ray irradiation of mice, DNA damage markers, γ-H2AX and p53BP1, increased by 10, 15 and 5-fold in different region of the brain, while cleaved caspase 3 signaling molecule increased by 1.4 and 2.6-fold (Gionchiglia et al., 2021). Gamma ray irradiation of Wistar rats showed a 6-fold increase in DNA damage marker compared to a 0.2-fold decrease in (B-cell lymphoma 2) Bcl-2 and a 2- to 4-fold increase in signaling proteins p53, Bcl-2-associated protein X (Bax) and caspase 3/8/9 (El-Missiry et al., 2018).

Essentiality

Some studies show that preventing an increase in DNA strand breaks will restore signaling. Treatment with mesenchymal stem cell- conditioned medium (MSC-CM) reduced γ-H2AX, decreased the levels of p53, Bax, cleaved caspase 3 and increased the levels of Bcl-2 in HT22 cells irradiated with 10 Gy of X-rays (Huang et al., 2021). The inhibition of microRNA (miR)-711 decreased levels of DNA damage markers, p-ATM, p-ATR and γ-H2AX, and decreased signaling molecules including p-p53, p21 and cleaved caspase 3 (Sabirzhanov et al., 2020).

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

None identified

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Modulating Factor	Details	Effects on the KER	References
Nitroxides	Increased concentration	Decreased DNA strand breaks.	DeGraff et al., 1992; Citrin & Mitchel, 2014
5-fluorouracil	Increased concentration	Increased DNA strand breaks.	De Angelis et al., 2006; Citrin & Mitchel, 2014
Thiols	Increased concentration	Decreased DNA strand breaks.	Milligan et al., 1995; Citrin & Mitchel, 2014
Cisplatin	Increased concentration	Decreased DNA break repair.	Sears & Turchi; Citrin & Mitchel, 2014

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

The tables below provide some representative examples of quantitative linkages between the two key events. All data that is represented is statistically significant unless otherwise indicated.

Dose Concordance

Reference	Experiment Description	Result
Sabirzhanov et al., 2020	In vitro. Rat cortical neurons were exposed to 2, 8 and 32 Gy X-rays. DNA damage was determined by γ-H2AX staining and western blot analysis of p-ATM and p-ATR. Altered signaling was determined by levels of p-p53, p21, cleaved caspase 3, measured by Western blot.	Irradiated primary cortical neurons showed increased γ-H2AX by 30-fold at both 8 and 32 Gy but not at 2 Gy. p-ATM was increased at all doses, increasing about 15-fold at 8 and 32 Gy. Signaling molecules including p-p53, p21, and cleaved caspase 3 were increased at all doses.
Ungvari et al., 2013	In vitro. CMVECs and rat hippocampal neurons were irradiated with 137Cs gamma rays. DNA strand breaks were assessed with the comet assay. Caspase 3/7 activity was determined by an assay kit.	DNA damage increased at all doses (2-10 Gy). In the control, less than 5% of DNA content was in the tail while by 6 Gy 35% of the DNA content was in the tail in CMVECs and 25% was in the tail in neurons. In CMVECs, 2, 4, and 6 Gy increased caspase 3/7 activity 5- to 6-fold.

Time Concordance

Reference	Experiment Description	Result
Zhang et al., 2017	In vitro. HT22 cells were irradiated with 12 Gy of X-rays (1.16 Gy/min). p-ATM, γ-H2AX, cleaved caspase 3 and p53 were measured with Western blot.	p-ATM and γ-H2AX were increased 4.4-fold and 3.2- fold, respectively, 30 min after 12 Gy. p53 was increased 4.6-fold at 1 h post-irradiation. A 9-fold increase in cleaved caspase 3 was observed 48 h post-irradiation.
Gionchiglia et al., 2021	In vivo. CD1 and B6/129 mice were irradiated with 10 Gy of X-rays. γ-H2AX and 53BP1 foci were quantified with immunofluorescence in neurons. Cleaved caspase 3 positive neurons were measured with immunofluorescence.	At both 15 and 30 min post-irradiation, γ-H2AX and p53BP1 foci increased. However, cleaved caspase 3 increased at 30 min but not at 15 min.
Sabirzhanov et al., 2020	In vitro. Rat cortical neurons were exposed to 2, 8 and 32 Gy X-rays. DNA damage was determined by γ-H2AX staining and western blot analysis of p-ATM and p-ATR. Altered signaling was determined by levels of p-p53, p21, cleaved caspase 3, measured by Western blot.	DNA damage occurred as early as 30 min post 8 Gy irradiation, indicated by increased p-ATM, γ-H2AX and p-ATR. Signaling molecules p-p53, p21 and cleaved caspase 3 increased at 3 or 6h post-irradiation.
Park et al., 2022	In vitro. Human aortic endothelial cells (HAECs) were irradiated with 4 Gy of 137Cs gamma rays (3.5 Gy/min). γ-H2AX was measured with western blot. p-ATM and 53BP1 were determined with immunofluorescence. p-p53 and p21 were measured with Western blot.	γ-H2AX, p-ATM, and 53BP1 increased at 1 h post-irradiation, while p-p53 and p21 were increased at 6 h post-irradiation.
Kim et al., 2014	In vitro. Human umbilical vein endothelial cells (HUVECs) were irradiated with 4 Gy 137Cs gamma rays. DNA damage was determined by γ-H2AX. p21 and p53 were measured by Western blot.	γ-H2AX foci greatly increased at 1 and 6 h post-irradiation, while p-p53 and p21 were increased at 6 h post-irradiation.
Ungvari et al., 2013	In vitro. CMVECs and rat hippocampal neurons were irradiated with 2-6 Gy of 137Cs gamma rays. DNA strand breaks were assessed with the comment assay. Caspase 3/7 activity was determined by an assay kit.	DNA damage in neurons and CMVECs increased at 1 h post-irradiation, while caspase 3/7 activity increased the greatest at 18 h post-irradiation in CMVECs.
Lafargue et al., 2017	In vitro. HMVEC-L were irradiated with 15 Gy of X-rays. γ-H2AX foci were assessed with immunofluorescence. p-ATM and ATM were assessed with Western blot. Signaling proteins including p53, p21 and p16 were assessed with western blot.	Without irradiation, most cells had 0 or 1 γ-H2AX foci, while 14 days after 15 Gy, most cells had 2-6 γ-H2AX foci. The ratio of p-ATM/ATM was also increased 14 days after 15 Gy. p53, p21, and p16 were all increased at 21 days after 15 Gy.

Incidence Concordance

Reference	Experiment Description	Result
El-Missiry et al., 2018	In vivo. Wistar rats were irradiated with 4 Gy of 137Cs gamma rays (0.695 cGy/s). DNA damage was assessed with a comet assay. Multiple signaling proteins were assessed with assay kits.	The tail moment increased 6-fold while signaling proteins including p53, Bax, and caspases 3/8/9 increased 2- to 4-fold, and Bcl-2 decreased 0.2-fold.
Gionchiglia et al., 2021	In vivo. CD1 and B6/129 mice were irradiated with 10 Gy of X-rays. γ-H2AX and 53BP1 foci were quantified with immunofluorescence. Cleaved caspase 3 positive cells were measured with immunofluorescence.	γ-H2AX and p53BP1 foci increased about 10-fold in the forebrain and cerebral cortex, about 15-fold in the hippocampus and about 5-fold in the subventricular zone (SVZ)/ rostral migratory stream (RMS)/ olfactory bulb (OB). Cleaved caspase 3 increased 1.4-fold in the cerebral cortex and hippocampus and 2.6-fold in the SVZ/RMS/OB.

Known Modulating Factors

Modulating Factor	Details	Effects on the KER	References
Nitroxides	Increased concentration	Decreased DNA strand breaks.	DeGraff et al., 1992; Citrin & Mitchel, 2014
5-fluorouracil	Increased concentration	Increased DNA strand breaks.	De Angelis et al., 2006; Citrin & Mitchel, 2014
Thiols	Increased concentration	Decreased DNA strand breaks.	Milligan et al., 1995; Citrin & Mitchel, 2014
Cisplatin	Increased concentration	Decreased DNA break repair.	Sears & Turchi; Citrin & Mitchel, 2014

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Not identified

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Evidence for this relationship is predominantly from studies using rat- and mouse-derived cells, with some in vivo evidence in mice and rats. There is in vivo evidence in male animals, but no in vivo studies specify the use of female animals. In vivo evidence is from adult models.

References

List of the literature that was cited for this KER description. More help

Agrawala, P.K. et al. (2008), "Induction and repairability of DNA damage caused by ultrasoft X-rays: Role of core events.", Int. J. Radiat. Biol., 84(12):1093–1103. doi:10.1080/09553000802478083.

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, United States, https://doi.org/10.1667/RADE-20-00284.1

Ainsbury, E. A. et al. (2016), “Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research”, Mutation research. Reviews in mutation research, Vol. 770, Elsevier B.V., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.07.010

Alexander, J. L. and Orr-Weaver, T. L. (2016), “Replication fork instability and the consequences of fork collisions from replication”, Genes & Development, Vol. 30/20, Cold Spring Harbor Laboratory Press, https://doi.org/ 10.1101/gad.288142.116

Allen, C. H. et al. (2018), “Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low-dose-range of ionizing radiation”, Physics in medicine & biology, Vol. 63/2, IOP Publishing, Bristol, https://doi.org/10.1088/1361-6560/aaa176

Antonelli, A.F. et al. (2015), "Induction and Repair of DNA DSB as Revealed by H2AX Phosphorylation Foci in Human Fibroblasts Exposed to Low- and High-LET Radiation: Relationship with Early and Delayed Reproductive Cell Death", Radiat. Res. 183(4):417-31, doi:10.1667/RR13855.1.

Acharya, M. et al. (2010), “Consequences of ionizing radiation-induced damage in human neural stem cells”, Free Radical Biology and Medicine. 49(12):1846-1855, doi:10.1016/j.freeradbiomed.2010.08.021.

Asaithamby, A. et al. (2008), "Repair of HZE-Particle-Induced DNA Double-Strand Breaks in Normal Human Fibroblasts.", Radiat Res. 169(4):437–446. doi:10.1667/RR1165.1.

Aufderheide, E. et al. (1987), “Heavy ion effects on cellular DNA: Strand break induction and repair in cultured diploid lens epithelial cells”, International journal of radiation biology and related studies in physics, chemistry and medicine, Vol. 51/5, Taylor & Francis, London, https://doi.org/10.1080/09553008714551071

Bannik, K. et al. (2013), “Are mouse lens epithelial cells more sensitive to γ-irradiation than lymphocytes?”, Radiation and environmental biophysics, Vol. 52/2, Springer- Verlag, Berlin/Heidelberg, https://doi.org/10.1007/s00411-012-0451-8

Bains, S. K. et al. (2019), “Effects of ionizing radiation on telomere length and telomerase activity in cultured human lens epithelium cells”, International journal of radiation biology, Vol. 95/1, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2018.1466066

Barazzuol, L et al. (2017), “A coordinated DNA damage response promotes adult quiescent neural stem cell activation. PLOS Biology, 15(5). https://doi.org/10.1371/journal.pbio.2001264

Barnard, S. G. R. et al. (2018), “Dotting the eyes: mouse strain dependency of the lens epithelium to low dose radiation-induced DNA damage”, International journal of radiation biology, Vol. 94/12, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2018.1532609

Barnard, S. G. R. et al. (2019), “Inverse dose-rate effect of ionising radiation on residual 53BP1 foci in the eye lens”, Scientific Reports, Vol. 9/1, Nature Publishing Group, England, https://doi.org/10.1038/s41598-019-46893-3

Barnard, S. G. R. et al. (2022), “Radiation-induced DNA damage and repair in lens epithelial cells of both Ptch1 (+/-) and Ercc2 (+/-) mutated mice”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, https://doi.org/10.1667/RADE-20-00264.1

Baselet, B. et al. (2019), “Pathological effects of ionizing radiation: endothelial activation and dysfunction”, Cellular and molecular life sciences, Vol. 76/4, Springer Nature, https://doi.org/10.1007/s00018-018-2956-z

Baselet, B. et al. (2017), “Functional Gene Analysis Reveals Cell Cycle Changes and Inflammation in Endothelial Cells Irradiated with a Single X-ray Dose”, Frontiers in pharmacology, Vol. 8, Frontiers, https://doi.org/10.3389/fphar.2017.00213

Baumstark-Khan, C., J. Heilmann, and H. Rink (2003), ‘Induction and repair of DNA strand breaks in bovine lens epithelial cells after high LET irradiation”, Advances in space research, Vol. 31/6, Elsevier Ltd, England, https://doi.org/10.1016/S0273-1177(03)00095-4

Beels, L. et al. (2009), "g-H2AX Foci as a Biomarker for Patient X-Ray Exposure in Pediatric Cardiac Catheterization", Are We Underestimating Radiation Risks?":1903– 1909. doi:10.1161/CIRCULATIONAHA.109.880385.

Belli M, Cherunbini R, Vecchia MD, Dini V, Moschini G, Signoretti C, Simon G, Tabocchini MA, Tiveron P. 2000. DNA DSB induction and rejoining in V79 cells irradiated with light ions: a constant field gel electrophoresis study. Int J Radiat Biol. 76(8):1095-1104.

Brooks, A.L., D.G. Hoel & R.J. Preston (2016), "The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.", Int. J. Radiat. Biol. 92(8):405–426. doi:10.1080/09553002.2016.1186301.

Bucolo, C. et al. (1994), “The effect of ganglioside on oxidation-induced permeability changes in lens and in epithelial cells of lens and retina”, Experimental eye research,

Vol. 58/6, Elsevier Ltd, London, https://doi.org/10.1006/exer.1994.1067

Cabrera et al. (2011), “Antioxidants and the integrity of ocular tissues”, in Veterinary medicine international, SAGE-Hindawi Access to Research, United States. DOI: 10.4061/2011/905153

Cadet, J. et al. (2012), “Oxidatively generated complex DNA damage: tandem and clustered lesions”, Cancer letters, Vol. 327/1, Elsevier Ireland Ltd, Ireland. https://doi.org/10.1016/j.canlet.2012.04.005

Cannan, W.J. & D.S. Pederson (2016), "Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin.", J. Cell Physiol. 231(1):3–14. doi:10.1002/jcp.25048.

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

Chadwick, K.H., (2017), Towards a new dose and dose-rate effectiveness factor (DDREF)? Some comments., J Radiol Prot., 37:422-433. doi: 10.1088/1361-6498/aa6722.

Charlton, D.E., H. Nikjoo & J.L. Humm (1989), "Calculation of initial yields of single- and double-strand breaks in cell nuclei from electrons, protons and alpha particles.", Int.

J. Rad. Biol., 53(3):353-365, DOI: 10.1080/09553008814552501

Christensen, D.M. (2014), "Management of Ionizing Radiation Injuries and Illnesses, Part 3: Radiobiology and Health Effects of Ionizing Radiation.", 114(7):556–565. doi:10.7556/jaoa.2014.109.

Citrin, D.E. & J.B. Mitchel (2014), "Public Access NIH Public Access.", 71(2):233–236. doi:10.1038/mp.2011.182.doi.

Dalke, C. et al. (2018), “Lifetime study in mice after acute low-dose ionizing radiation: a multifactorial study with special focus on cataract risk”, Radiation and environmental biophysics, Vol. 57/2, Springer Berlin Heidelberg, Berling/Heidelberg, https://doi.org/10.1007/s00411-017-0728-z

Day, T.K. et al. (2007), "Adaptive Response for Chromosomal Inversions in pKZ1 Mouse Prostate Induced by Low Doses of X Radiation Delivered after a High Dose.", Radiat Res. 167(6):682–692. doi:10.1667/rr0764.1.

De Angelis, P. M. et al. (2006), “Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery”, Molecular Cancer, Vol. 5/20, BioMed Central, https://doi.org/10.1186/1476-4598-5-20

DeGraff, W. G. et al. (1992), “Nitroxide-mediated protection against X-ray- and neocarzinostatin-induced DNA damage”, Free Radical Biology and Medicine, Vol. 13/5, Elsevier, https://doi.org/10.1016/0891-5849(92)90142-4

Desouky, O., N. Ding & G. Zhou (2015), "ScienceDirect Targeted and non-targeted effects of ionizing radiation.", J. Radiat. Res. Appl. Sci. 8(2):247–254. doi:10.1016/j.jrras.2015.03.003.

Dong 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, 91(3):224–239. https://doi.org/10.3109/09553002.2014.988895

Dong, X. et al. (2014), “NEMO modulates radiation-induced endothelial senescence of human umbilical veins through NF-κB signal pathway”, Radiation Research, Vol. 183/1, BioOne, https://doi.org/10.1667/RR13682.1

Dubrova, Y.E. & M.A. Plumb (2002), "Ionising radiation and mutation induction at mouse minisatellite loci The story of the two generations", Mutat. Res. 499(2):143–150. EPRI (2014), Epidemiology and mechanistic effects of radiation on the lens of the eye: Review and scientific appraisal of the literature, EPRI, California

Falk, M., E. Lukášová & S. Kozubek (2008), "Chromatin structure influences the sensitivity of DNA to γ-radiation.", Biochim. Biophys. Acta. - Mol. Cell. Res. 1783(12):2398– 2414. doi:10.1016/j.bbamcr.2008.07.010.

Feinendegen, L.E. (2005), "UKRC 2004 debate Evidence for beneficial low level radiation effects and radiation hormesis. Radiology.", 78:3–7. doi:10.1259/bjr/63353075. Feinendegen, L.E., M. Pollycove & R.D. Neumann (2007), "Whole-body responses to low-level radiation exposure: New concepts in mammalian radiobiology.", Exp.

Hematol. 35(4 SUPPL.):37–46. doi:10.1016/j.exphem.2007.01.011.

Flegal, M. et al. (2015), "Measuring DNA Damage and Repair in Mouse Splenocytes After Chronic In Vivo Exposure to Very Low Doses of Beta- and γ-Radiation.", (July):1–

9. doi:10.3791/52912.

Foray, N., M. Bourguignon and N. Hamada (2016), “Individual response to ionizing radiation”, Mutation research. Reviews in mutation research, Vol. 770, Elsevier B.V., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.09.001

Franken NAP, Hovingh S, Cate RT, Krawczyk P, Stap J, Hoebe R, Aten J, Barendsen GW. 2012. Relative biological effectiveness of high linear energy transfer alpha- particles for the induction of DNA-double-strand breaks, chromosome aberrations and reproductive cell death in SW-1573 lung tumour cells. Oncol reports. 27:769-774.

Frankenberg D, Brede HJ, Schrewe UJ, Steinmetz C, Frankenberg-Scwager M, Kasten G, Pralle E. 1999. Induction of DNA Double-Strand Breaks by 1H and 4He Ions in Primary Human Skin Fibroblasts in the LET range of 8 to 124 keV/µm. Radiat Res. 151:540-549.

Geisel, D. et al. (2012), “DNA double-strand breaks as potential indicators for the biological effects of ionising radiation exposure from cardiac CT and conventional coronary angiography: a randomised, controlled study”, European Radiology, Vol. 22/8, Springer Nature, https://doi.org/10.1007/s00330-012-2426-1

Gionchiglia, N. et al. (2021), “Association of Caspase 3 Activation and H2AX γ Phosphorylation in the Aging Brain: Studies on Untreated and Irradiated Mice,” Biomedicines. 9(9):1166. doi: 10.3390/biomedicines9091166.

Goodhead, D.T. (2006), "Energy deposition stochastics and track structure: What about the target?", Radiat. Prot. Dosimetry. 122(1–4):3–15. doi:10.1093/rpd/ncl498.

Grudzenski, S. et al. (2010), "Inducible response required for repair of low-dose radiation damage in human fibroblasts.", Proc. Natl. Acad. Sci. USA. 107(32): 14205-14210, doi:10.1073/pnas.1002213107.

Hada, M. & A.G. Georgakilas (2008), "Formation of Clustered DNA Damage after High-LET Irradiation: A Review.", J. Radiat. Res., 49(3):203–210. doi:10.1269/jrr.07123.

Hamada, N. et al. (2006), “Histone H2AX phosphorylation in normal human cells irradiated with focused ultrasoft X rays: evidence for chromatin movement during repair”, Radiation Research, Vol. 166/1, Radiation Research Society, United States, https://doi.org/10.1667/RR3577.1

Hamada, N. (2014), “What are the intracellular targets and intratissue target cells for radiation effects?”, Radiation research, Vol. 181/1, The Radiation Research Society, Lawrence, https://doi.org/10.1667/RR13505.1

Hamada, N. and T. Sato (2016), “Cataractogenesis following high-LET radiation exposure”, Mutation Research. Reviews in mutation research, Vol. 770, Elsevier B.V., Amsterdam, https://doi.org/10.1016/j.mrrev.2016.08.005

Hamada, N. (2017a), “Ionizing radiation sensitivity of the ocular lens and its dose rate dependence”, International journal of radiation biology, Vol. 93/10, Taylor & Francis, Abingdon, https://doi.org/10.1080/09553002.2016.1266407

Hamada, N. (2017b), “Ionizing radiation response of primary normal human lens epithelial cells”, PloS ONE, Vol. 12/7, Public Library Science, San Francisco, https://doi.org/10.1371/journal.pone.0181530

Havas, M. (2017), “When theory and observation collide: Can non-ionizing radiation cause cancer?”, Environmental pollution, Vol. 221, Elsevier Ltd, England. https://doi.org/10.1016/j.envpol.2016.10.018

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

Iliakis, G., T. Murmann & A. Soni (2015), "Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations.", Mutat. Res. - Genet. Toxicol. Environ. Mutagen. 793:166–175. doi:10.1016/j.mrgentox.2015.07.001.

Joiner, M. (2009), "Basic Clinical Radiobiology", Edited by. [1] P.J. Sadler, Next-Generation Met Anticancer Complexes Multitargeting via Redox Modul Inorg Chem 52

21.:375. doi:10.1201/b13224.

Jorge, S.-G. et al. (2012), "Evidence of DNA double strand breaks formation in Escherichia coli bacteria exposed to alpha particles of different LET assessed by the SOS response.", Appl. Radiat. Isot. 71(SUPPL.):66–70. doi:10.1016/j.apradiso.2012.05.007.

Kadhim, M.A., M.A. Hill & S.R. Moore, (2006), "Genomic instability and the role of radiation quality.", Radiat. Prot. Dosimetry. 122(1–4):221–227. doi:10.1093/rpd/ncl445. Khanna, K.K. & S.P. Jackson (2001), "DNA double-strand breaks: signaling, repair and the cancer connection.", Nature Genetics. 27(3):247-54. doi:10.1038/85798.

Kim, K. S. et al. (2014), “Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells”, International Journal of Radiation Biology, Vol. 90/1, Informa, London, https://doi.org/10.3109/09553002.2014.859763

Kim, J. N. and B. M. Lee (2007), “Risk factors, health risks, and risk management for aircraft personnel and frequent flyers”, Journal of toxicology and environmental health. Part B, Critical reviews, Vol. 10/3, Taylor & Francis Group, Philadelphia, https://doi.org/10.1080/10937400600882103

Kleiman, N. J., R. Wang and A. Spector (1990), “Ultraviolet light induced DNA damage and repair in bovine lens epithelial cells”, Current eye research, Vol. 9/12, Informa UK Ltd, Oxford, https://doi.org/10.3109/02713689009003475

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, 1–12. https://doi.org/10.1080/09553002.2022.2110306

Kuefner, M.A. et al. (2009), "DNA Double-Strand Breaks and Their Repair in Blood Lymphocytes of Patients Undergoing Angiographic Procedures.", Investigative radiology. 44(8):440-6. doi:10.1097/RLI.0b013e3181a654a5.

Kuefner, M.A. et al. (2015), "Chemoprevention of Radiation-Induced DNA Double-Strand Breaks with Antioxidants.", Curr Radiol Rep (2015) 3: 81. https://doi.org/10.1007/s40134-014-0081-9

Kuhne, M., G. Urban & M. Lo, (2005), "DNA Double-Strand Break Misrejoining after Exposure of Primary Human Fibroblasts to CK Characteristic X Rays, 29 kVp X Rays and Co γ-Rays.", Radiation Research. 164(5):669-676. doi:10.1667/RR3461.1.

de Lara, C.M. et al. (2001), "Dependence of the Yield of DNA Double-Strand Breaks in Chinese Hamster V79-4 Cells on the Photon Energy of Ultrasoft X Rays.", Radiation Research. 155(3):440-8. doi:10.1667/0033-7587(2001)155[0440:DOTYOD]2.0.CO;2.

Liao, J. et al. (2011), “Anti-UVC irradiation and metal chelation properties of 6-benzoyl-5,7-dihydroxy-4-phenyl-chromen-2-one: An implications for anti-cataract agent”, International journal of molecular sciences, Vol. 12/10, MDPI, Basel. https://doi.org/10.3390/ijms12107059

Lipman, R. M., B. J. Tripathi, R. C. Tripathi (1998), “Cataracts induced by microwave and ionizing radiation”, Survey of ophthalmology, Vol. 33/3, Elsevier Inc, United States, https://doi.org/10.1016/0039-6257(88)90088-4

Lomax, M.E., L.K. Folkes & P.O. Neill (2013). "Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy", Statement of Search Strategies Used and Sources of Information Why Radiation Damage is More Effective than Endogenous Damage at Killing Cells Ionising Radiation-induced Do. 25:578–585. doi:10.1016/j.clon.2013.06.007.

Long, A. C., C. M. H. Colitz, and J. A. Bomser (2001), “Apoptotic and necrotic mechanisms of stress-induced human lens epithelial cell death”, Experimental biology and medicine, SAGE Publications, London, https://doi.org/10.1177/153537020422901012

Lorat, Y. et al. (2015), "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy – The heavy burden to repair.", DNA Repair (Amst). 28:93–106. doi:10.1016/j.dnarep.2015.01.007.

Maier, P. et al. (2016), "Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization.", Int. J. Mol. Sci., 14;17(1), pii:E102, doi:10.3390/ijms17010102.

Markiewicz, E. et al. (2015), “Nonlinear ionizing radiation-induced changes in eye lens cell proliferation, cyclin D1 expression and lens shape”, Open biology, Vol. 5/4, Royal society, London, https://doi.org/10.1098/rsob.150011

Milligan, J. R. et al. (1995), « DNA repair by thiols in air shows two radicals make a double-strand break”, Radiation Research, Vol 143/3, pp. 273-280

Moore, S., F.K.T. Stanley & A.A. Goodarzi (2014), "The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation – No simple task.", DNA repair (Amst), 17:64–73. doi: 10.1016/j.dnarep.2014.01.014.

Mosconi, M., U. Giesen & F. Langner (2011), "53BP1 and MDC1 foci formation in HT-1080 cells for low- and high-LET microbeam irradiations.", Radiat. Envrion. Biophys. 50(3):345–352. doi:10.1007/s00411-011-0366-9.

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

Nenoi, M., B. Wang & G. Vares (2015), "In vivo radioadaptive response: A review of studies relevant to radiation-induced cancer risk.", Hum. Exp. Toxicol. 34(3):272–283.

doi:10.1177/0960327114537537.

Nikitaki, Z. et al. (2016), "Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET).", Free Radiac. Res. 50(sup1):S64-S78, doi:10.1080/10715762.2016.1232484.

Nikjoo, H. et al. (2001), "Computational approach for determining the spectrum of DNA damage induced by ionizing radiation.", Radiat. Res. 156(5 Pt 2):577–83.

Nübel, T. et al. (2006), “Lovastatin protects human endothelial cells from killing by ionizing radiation without impairing induction and repair of DNA double-strand breaks”, Clinical Cancer Research, Vol. 12/3, American Association for Cancer Research, https://doi.org/10.1158/1078-0432.CCR-05-1903

Ojima, M., N. Ban, and M. Kai (2008), “DNA double-strand breaks induced by very low X-ray doses are largely due to bystander effects”, Radiation Research, Vol. 170/3, Radiation Research Society, United States, https://doi.org/10.1667/RR1255.1

Okayasu, R. (2012a), "Repair of DNA damage induced by accelerated heavy ions-A mini review.", Int. J. Cancer. 130(5):991–1000. doi:10.1002/ijc.26445. Okayasu, R. (2012b), "Heavy ions — a mini review.", 1000:991–1000. doi:10.1002/ijc.26445.

Park, J. W. et al. (2022), “Metformin alleviates ionizing radiation-induced senescence by restoring BARD1-mediated DNA repair in human aortic endothelial cells”, Experimental Gerontology, Vol. 160, Elsevier, Amsterdam, https://doi.org/10.1016/j.exger.2022.111706

Parris, C.N. et al. (2015), "Enhanced γ-H2AX DNA damage foci detection using multimagnification and extended depth of field in imaging flow cytometry.", Cytom. Part A. 87(8):717–723. doi:10.1002/cyto.a.22697.

Radulescu I., K. Elmroth & B. Stenerlöw (2006), "Chromatin Organization Contributes to Non-randomly Distributed Double-Strand Breaks after Exposure to High-LET Radiation.", Radiat. Res. 161(1):1–8. doi:10.1667/rr3094.

Rastogi, R. P. et al. (2010), “Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair”, Journal of nucleic acids, Hindawi Ltd, United States. https://doi.org/10.4061/2010/592980

Reddy, V. N. et al. (1998), “The effect of aqueous humor ascorbate on ultraviolet-B-induced DNA damage in lens epithelium”, Investigative ophthalmology & visual science, Vol. 39/2, Arvo, pp. 344-350

Rogakou, E.P. et al. (1999), "Megabase Chromatin Domains Involved in DNA Double-Strand Breaks In Vivo.", J. Cell Biol, 146(5):905-16. doi: 10.1083/jcb.146.5.905.

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. 78/5, Elsevier Ltd, London, https://doi.org/10.1016/j.exer.2003.12.011

Rombouts, C. et al. (2013), “Differential response to acute low dose radiation in primary and immortalized endothelial cells”, International Journal of Radiation Biology, Vol. 89/10, Informa, London, https://doi.org/10.3109/09553002.2013.806831

Rothkamm, K. et al. (2015), "Review DNA Damage Foci: Meaning and Significance.", Environ. Mol. Mutagen., 56(6):491-504, doi: 10.1002/em.21944.

Rothkamm, K. & M. Lo (2003), "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses.", PNAS, 100(9):5057-62. doi:10.1073/pnas.0830918100.

Rübe, C.E. et al. (2008), "Cancer Therapy: Preclinical DNA Double-Strand Break Repair of Blood Lymphocytes and Normal Tissues Analysed in a Preclinical Mouse Model: Implications for Radiosensitivity Testing.", Clin. Cancer Res., 14(20):6546–6556. doi:10.1158/1078-0432.CCR-07-5147.

Russo, A. et al. (2015), "Review Article Genomic Instability: Crossing Pathways at the Origin of Structural and Numerical Chromosome Changes.", Envrion. Mol. Mutagen. 56(7):563-580. doi:10.1002/em.

Rydberg B, Heilbronn L, Holley WR, Lobrich M, Zeitlin C et al. 2002. Spatial Distribution and Yield of DNA Double-Strand Breaks Induced by 3-7 MeV Helium Ions in Human Fibroblasts. Radiat Res. 158(1):32-42.

Sabirzhanov, et al. (2020), “Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways.”, Int J Mol Sci. 21(15):5239. doi: 10.3390/ijms21155239.

Sage, E. & N. Shikazono (2017), "Free Radical Biology and Medicine Radiation-induced clustered DNA lesions: Repair and mutagenesis.", Free Radic. Biol. Med. 107(December 2016):125–135. doi:10.1016/j.freeradbiomed.2016.12.008.

Sasaki, H. et al. (1998), “TEMPOL protects against lens DNA strand breaks and cataract in the x-rayed rabbit”, Investigative ophthalmology & visual sciences, Vol. 39/3, Arvo, Rockville, pp. 544-552

Schmal, Z. et al. (2019), “DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis”, Radiotherapy and Oncology. 137:45-

54. doi:10.1016/j.radonc.2019.04.021.

Sears, C. R. and J. J. Turchi (2012), “Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) independent of downstream damage response (DDR) pathways”, Journal of biological chemistry, Vol 287/29, The American Society for Biochemistry and Molecular Biology, Inc, USA, https://doi.org/ 10.1074/jbc.M112.344911

Shah, D.J., R.K. Sachs & D.J. Wilson (2012), "Radiation-induced cancer: A modern view." Br. J. Radiol. 85(1020):1166–1173. doi:10.1259/bjr/25026140.

Shelke, S. & B. Das (2015), "Dose response and adaptive response of non- homologous end joining repair genes and proteins in resting human peripheral blood mononuclear cells exposed to γ radiation.", (December 2014):365–379. doi:10.1093/mutage/geu081.

Sidjanin, D., S. Zigman and J. Reddan (1993), “DNA damage and repair in rabbitlens epithelial cells following UVA radiation”, Current eye research, Vol. 12/9, Informa UK Ltd, Oxford, https://doi.org/10.3109/02713689309020382

Smith, J. et al. (2003), "Impact of DNA ligase IV on the delity of end joining in human cells.", Nucleic Acids Research. 31(8):2157-2167.doi:10.1093/nar/gkg317.

Smith, T.A. et al. (2017), "Radioprotective agents to prevent cellular damage due to ionizing radiation." Journal of Translational Medicine.15(1).doi:10.1186/s12967-017-1338- x.

Stewart, F. A. et al. (2012), “ICRP publication 118: ICRP statement on tissue reactions and early and late effects of radiation in normal tissues and organs – threshold doses

for tissue reactions in a radiation protection context”, Annals of the ICRP, Vol, 41/1-2, Elsevier Ltd, London, https://doi.org/10.1016/j.icrp.2012.02.001

Sudprasert, W., P. Navasumrit & M. Ruchirawat (2006), "Effects of low-dose γ radiation on DNA damage, chromosomal aberration and expression of repair genes in human blood cells.", Int. J. Hyg. Envrion. Health, 209:503–511. doi:10.1016/j.ijheh.2006.06.004.

Sutherland, B.M. et al. (2000), "Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation.", J. of Rad. Res. 43 Suppl(S):S149-

52. doi: 10.1269/jrr.43.S149

Sylvester, C. B. et al. (2018), “Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer”, Frontiers in cardiovascular medicine, Vol. 5, Frontiers, https://doi.org/10.3389/fcvm.2018.00005

Terato, H. & H. Ide (2005), "Clustered DNA damage induced by heavy ion particles.", Biol. Sci. Sp. 18(4):206–215. doi:10.2187/bss.18.206.

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

Valentin, J.D.J (1998), "Chapter 1. Ann ICRP.", 28(4):5–7. doi:10.1016/S0146-6453(00)00002-6. http://www.ncbi.nlm.nih.gov/pubmed/10882804.

Venkatesh, P. et al. (2016), "Effect of chromatin structure on the extent and distribution of DNA double strand breaks produced by ionizing radiation; comparative study of hESC and differentiated cells lines.", Int J. Mol. Sci. 17(1). doi:10.3390/ijms17010058.

Wang, et al. (2021), “Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms.”, Cells. 10(12):3570. doi: 10.3390/cells10123570

Ward, J. F. (1988), "DNA Damage Produced by Ionizing Radiation in Mammalian Cells: Identities, Mechanisms of Formation, and Reparability.", Prog. Nucleic Acid Res. Mol. Biol. 35(C):95–125. doi:10.1016/S0079-6603(08)60611-X.

Wolf, N. et al. (2008), “Radiation cataracts: Mechanisms involved in their long delayed occurrence but then rapid progression”, Molecular vision, Vol. 14/34-35, Molecular Vision, Atlanta, pp. 274-285

Wu, L.J. et al. (1999), "Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells.", Proc. Natl. Acad. Sci. 96(9):4959–4964. doi:10.1073/pnas.96.9.4959.

Yamaguchi, H. et al. (2005), "Estimation of Yields of OH Radicals in Water Irradiated by Ionizing Radiation.", J. of Rad. Res. 46(3):333-41. doi: 10.1269/jrr.46.333.

Zhang, L. et al. (2017), “The inhibitory effect of minocycline on radiation-induced neuronal apoptosis via AMPKα1 signaling-mediated autophagy.”, Sci Rep.7(1):16373. doi: 10.1038/s41598-017-16693-8.