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Relationship: 1589

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

Increased transcription of genes encoding acute phase proteins leads to Systemic acute phase response

Upstream event

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

Increased transcription of genes encoding acute phase proteins

Downstream event

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

Systemic acute phase response

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
Substance interaction with lung resident cell membrane components leading to atherosclerosis	adjacent	High	Moderate	Ulla Vogel (send email)	Under development: Not open for comment. Do not cite	Under Development

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
mouse	Mus musculus	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	High
Female	High

Life Stage Applicability

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

Term	Evidence
All life stages	High

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

This KER presents the association between the increased transcription of genes encoding acute phase proteins (Key event 1438) in different tissues and the induction of systemic acute phase response (Key event 1439). Acute phase proteins are expressed in the liver, and in several other tissues including lung (Gabay & Kushner, 1999; Hadrup et al., 2020; NCBI, 2023; Saber et al., 2014; Urieli-Shoval et al., 1998). During acute phase response several changes occur, including variations in plasma concentration of acute phase proteins. The two major acute phase proteins are C-reactive protein and serum amyloid A (Gabay & Kushner, 1999). The evidence of the KER presented is based on animal studies (mice).

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

The evidence for this KER was mainly based on novel experimentation and literature search on the search engine PubMed. The first part of the relationship was assessed using gene expression analysis, while the second part of the relationship was assessed through the measurement of protein levels in blood plasma or serum.

Evidence Supporting this KER

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

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

The biological plausibility is high. After gene expression of acute phase proteins in tissues during inflammatory conditions, mRNA is translated and folded into proteins (Alberts, 2017). These proteins are then release to the systemic circulation (Van Eeden, Leipsic, Paul Man, & Sin, 2012).

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

The table below presents evidence for this KER. The transcription of genes encoding acute phase proteins was measured in tissues (Key event 1438), while systemic acute phase response is measured as the concentration of acute phase proteins in blood plasma or serum (Key event 1439).

Species	Stressor	Transcription of genes encoding acute phase proteins	Systemic acute phase response	Reference
Mouse	Carbon black nanoparticles	Yes, significant Saa1, Saa2 and Saa3 gene expression increase in lung tissue, at days 1, 3 and 28 after exposure. Saa3 gene expression increase in liver tissue at day 1 after exposure.	Yes, significant increase of plasma serum amyloid A (SAA) at 1 and 28 days after exposure.	(Bourdon et al., 2012)
Mouse	Multiwalled carbon nanotubes (referred as CNT_small)	Yes, increased differential expression of acute phase response genes in liver tissue 1 and 3 days after exposure to 162 µg. Increased differential expression of acute phase response genes in lung tissue 3 days after exposure to 18 and 162 µg, and 1 and 3 days after exposure to 54 µg.	Yes, increased plasma SAA3 1, 3 and 28 days after exposure to 162 µg, and 3 days after exposure to 18 and 54 µg.	(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015)
Mouse	Multiwalled carbon nanotubes (referred as CNT_large)	Yes, increased differential expression of acute phase response genes in liver tissue 1 and 3 days after exposure to 162 µg. Increased differential expression of acute phase response genes in lung tissue 1 and 3 days after exposure to 54 and 162 µg.	Yes, increased plasma SAA3 1 and 3 days after exposure to 162 µg, and 3 days after exposure to 54 µg.	(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015)
Mouse	Graphene oxide	Yes, increased mRNA expression of Saa3 in lung tissue, at all dose 1 and 3 days after exposure. Increased gene expression of Saa1 in liver tissue 1 day after exposure to 18 µg, and 3 days after exposure to 162 µg.	Yes, increased SAA3 plasma levels 3 days after exposure to 54 and 162 µg.	(Bengtson et al., 2017)
Mouse	Multiwalled carbon nanotubes	Yes, increased Saa1 mRNA expression in liver tissue 1 day after exposure to 18 and 54 µg. Increase in Saa1 mRNA levels in liver tissue 28 days exposure to 54 µg. Increased Saa3 mRNA expression in lung tissue 1 day after exposure to 6, 18 and 54 µg. Increase in Saa3 mRNA levels in lung tissue 28 days after 18 and 56 µg.	Yes, increased SAA1/2 and SAA3 plasma levels 1 day after exposure. No change in SAA1/2 and SAA3 28 and 92 days after exposure.	(Poulsen et al., 2017)
Mouse	Particulate matter from non-commercial airfield	Yes, increased expression of Saa3 mRNA in lung tissue and Saa1 mRNA in liver tissue after 1 day of exposure to 54 µg. No effect after 28 and 90 days.	Yes, increased plasma SAA3 levels after exposure to 54 µg after 3 days.	(Bendtsen et al., 2019)
Mouse	Diesel exhaust particles	Yes, increased expression of Saa3 mRNA in lung tissue after 1 day of exposure to 54 and 162 µg, and increased expression of Saa1 mRNA in liver tissue 1 day after exposure to 162 µg. No effect after 28 days.	Yes, increased plasma SAA3 levels after exposure to 54 µg, at 3 days.	(Bendtsen et al., 2019)
Mouse	Copper oxide	Yes, increased Saa3 mRNA expression in lung tissue 1 day after exposure to 2 and 6 µg. Increased Saa1 mRNA expression in liver tissue 1 day after exposure to 6 µg.	Yes, increased plasma SAA1/2 level after exposure to 6 µg, 1 day after exposure.	(Gutierrez et al., 2023)
Mouse	Tin dioxide	Yes, increased Saa3 mRNA expression in lung tissue and Saa1 mRNA expression in liver tissue, 1 day after exposure to 162 µg.	Yes, increased plasma SAA3 after exposure to 162 µg, 1 day after exposure.	(Gutierrez et al., 2023)
Mouse	Titanium dioxide	Yes, increased Saa3 mRNA expression in lung tissue and Saa1 mRNA expression in liver tissue 1 day after exposure.	Yes, increased plasma SAA3 and SAA1/2 after exposure to 162 µg, 1 day after exposure.	(Gutierrez et al., 2023)
Mouse	Carbon black	Yes, increased Saa3 mRNA expression in lung tissue 1 and 28 days after exposure. Increased Saa1 mRNA expression in liver tissue 1 day after exposure	Yes, increased plasma SAA3 and SAA1/2 after exposure to 162 µg, 1 day after exposure.	(Gutierrez et al., 2023)
Mouse	Singlewalled carbon nanotubes	Yes, increased SAA1, SAP and haptoglobin gene expression in liver tissue, 1 day after exposure.	Yes, increase serum CRP, haptoglobin and SAP 1 day after exposure.	(Erdely et al., 2011)
Mouse	Multiwalled carbon nanotubes	Yes, increased SAA1, SAP and haptoglobin gene expression in liver tissue, 1 day after exposure.	Yes, increase serum CRP, haptoglobin and SAP 1 day after exposure. No changes after 28 days.	(Erdely et al., 2011)
Mouse	Serum amyloid A	Yes, significantly increase of Saa3 mRNA levels in lung tissue and Saa1 mRNA levels in liver tissue.	Yes, increased levels of endogenous serum SAA3.	(Christophersen et al., 2021)

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

Although it is suggested that acute phase proteins are mainly produced in the liver (Gabay & Kushner, 1999), it has been shown that in mice, the liver has little upregulation of Saa genes after exposure to ultrafine carbon particles or diesel exhaust particle. In contrast, in the lung there is a marked expression of Saa3 mRNA (Saber et al., 2009, 2013).

Some studies show that the increase of Saa gene expression in lung or liver tissue does not translate into an increase in plasma SAA concentration (Bendtsen et al., 2019; Bengtson et al., 2017; Hadrup et al., 2019). This might be due to a protein concentration below the methods detection levels (Hadrup et al., 2019), while measuring gene expression provides a larger dynamic range.

The table below presents inconsistencies for this KER, where transcription of genes encoding acute phase proteins has been observed, while systemic acute phase response was not observed. The transcription of genes encoding acute phase proteins was measured in tissues, while systemic acute phase response is measured as the concentration of acute phase proteins in blood plasma or serum.

Species	Stressor	Transcription of genes encoding acute phase proteins	Systemic acute phase response	Reference
Mouse	Reduced graphene oxide	Yes, increased mRNA expression of Saa3 in lung tissue, 3 days after exposure to 162 µg. No changes in gene expression of Saa1 in liver tissue.	No, no change in serum amyloid A (SAA)3 plasma concentration 3 days after exposure.	(Bengtson et al., 2017)
Mouse	Particulate matter from commercial airport	Yes, increased expression of Saa3 mRNA in lung tissue after 1 day of exposure to 18 and 54 µg. No effect after 28 and 90 days.	No change in plasma SAA3.	(Bendtsen et al., 2019)
Mouse	Carbon black	Yes, increased expression of Saa3 mRNA in lung tissue at day 1 and day 90.	No change in plasma SAA3.	(Bendtsen et al., 2019)
Mouse	Uncoated zinc oxide nanoparticles	Yes, increase on Saa3 mRNA in lung tissue 1 day after exposure to 2 µg. No effect 3 and 28 days after exposure.	No effect on plasma SAA3.	(Hadrup et al., 2019)
Mouse	Coated zinc oxide nanoparticles	Yes, increase on Saa3 mRNA in lung tissue 1 day after exposure to 0.7 and 2 µg. No effect 3 and 28 days after exposure.	No effect on plasma SAA3.	(Hadrup et al., 2019)
Mouse	Zinc oxide	Yes, increased Saa1 mRNA expression in liver tissue 1 day after exposure to 0.7 µg. No change in Saa3 mRNA expression in lung tissue.	No change in plasma SAA3 or SAA1/2 levels.	(Gutierrez et al., 2023)

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

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

Response-response Relationship

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

The expression of Saa3 mRNA levels in lung tissue (Key event 1438) correlates with concentration of SAA3 plasma protein levels (Key event 1439), in female C57BL/6J mice 1 day after intratracheal instillation of metal oxide nanomaterials (Figure 1). The Pearson’s correlation coefficient was 0.89 (p<0.001) between log-transformed Saa3 mRNA levels in lung tissue and log-transformed SAA3 plasma protein levels (Gutierrez et al., 2023).

Figure 1. Correlations between Saa3 mRNA levels in lung tissue and SAA3 plasma protein levels in mice, 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).

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

After exposure to titanium dioxide nanoparticles in mice, expression of Saa1 mRNA in the liver is short lasting, while expression of Saa3 mRNA in lung tissue is longer lasting, as it has been observed 28 days after exposure (Wallin et al., 2017).

After exposure to multiwalled carbon nanotubes, it has been observed that expression of Saa1 and Saa3 in liver and lung tissue can be elevated 28 days after exposure, however in most cases there is no increase in plasma SAA1/2 nor SAA3 levels past day 1 after exposure (Poulsen et al., 2017).

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

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

Acute phase response is present in vertebrate species (Cray, Zaias, & Altman, 2009). In addition, serum amyloid A has been conserved in mammals throughout evolution and has been described in humans, mice, dogs, horses, among others (Uhlar & Whitehead, 1999).

References

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

Alberts, B. (2017). Molecular biology of the cell (Sixth edition.). CRC Press, an imprint of Garland Science. https://doi.org/10.1201/9781315735368

Bendtsen, K. M., Brostrom, A., Koivisto, A. J., Koponen, I., Berthing, T., Bertram, N., Kling, K. I., Dal Maso, M., Kangasniemi, O., Poikkimaki, M., Loeschner, K., Clausen, P. A., Wolff, H., Jensen, K. A., Saber, A. T., & Vogel, U. (2019). Airport emission particles: exposure characterization and toxicity following intratracheal instillation in mice. Part Fibre Toxicol, 16(1), 23. https://doi.org/10.1186/s12989-019-0305-5

Bengtson, S., Knudsen, K. B., Kyjovska, Z. O., Berthing, T., Skaug, V., Levin, M., Koponen, I. K., Shivayogimath, A., Booth, T. J., Alonso, B., Pesquera, A., Zurutuza, A., Thomsen, B. L., Troelsen, J. T., Jacobsen, N. R., & Vogel, U. (2017). Differences in inflammation and acute phase response but similar genotoxicity in mice following pulmonary exposure to graphene oxide and reduced graphene oxide. PLoS One, 12(6), e0178355. https://doi.org/10.1371/journal.pone.0178355

Bourdon, J. A., Halappanavar, S., Saber, A. T., Jacobsen, N. R., Williams, A., Wallin, H., Vogel, U., & Yauk, C. L. (2012). Hepatic and pulmonary toxicogenomic profiles in mice intratracheally instilled with carbon black nanoparticles reveal pulmonary inflammation, acute phase response, and alterations in lipid homeostasis. Toxicol Sci, 127(2), 474–484. https://doi.org/10.1093/toxsci/kfs119

Christophersen, D. V, Moller, P., Thomsen, M. B., Lykkesfeldt, J., Loft, S., Wallin, H., Vogel, U., & Jacobsen, N. R. (2021). Accelerated atherosclerosis caused by serum amyloid A response in lungs of ApoE(-/-) mice. FASEB J, 35(3), e21307. https://doi.org/10.1096/fj.202002017R

Cray, C., Zaias, J., & Altman, N. H. (2009). Acute phase response in animals: a review. Comp Med, 59(6), 517–526. https://www.ncbi.nlm.nih.gov/pubmed/20034426

Erdely, A., Liston, A., Salmen-Muniz, R., Hulderman, T., Young, S. H., Zeidler-Erdely, P. C., Castranova, V., & Simeonova, P. P. (2011). Identification of systemic markers from a pulmonary carbon nanotube exposure. J Occup Environ Med, 53(6 Suppl), S80-6. https://doi.org/10.1097/JOM.0b013e31821ad724

Gabay, C., & Kushner, I. (1999). Acute-phase proteins and other systemic responses to inflammation. N Engl J Med, 340(6), 448–454. https://doi.org/10.1056/NEJM199902113400607

Gutierrez, C. T., Loizides, C., Hafez, I., Brostrom, A., Wolff, H., Szarek, J., Berthing, T., Mortensen, A., Jensen, K. A., Roursgaard, M., Saber, A. T., Moller, P., Biskos, G., & Vogel, U. (2023). Acute phase response following pulmonary exposure to soluble and insoluble metal oxide nanomaterials in mice. Part Fibre Toxicol, 20(1), 4. https://doi.org/10.1186/s12989-023-00514-0

Hadrup, N., Rahmani, F., Jacobsen, N. R., Saber, A. T., Jackson, P., Bengtson, S., Williams, A., Wallin, H., Halappanavar, S., & Vogel, U. (2019). Acute phase response and inflammation following pulmonary exposure to low doses of zinc oxide nanoparticles in mice. Nanotoxicology, 13(9), 1275–1292. https://doi.org/10.1080/17435390.2019.1654004

Hadrup, N., Zhernovkov, V., Jacobsen, N. R., Voss, C., Strunz, M., Ansari, M., Schiller, H. B., Halappanavar, S., Poulsen, S. S., Kholodenko, B., Stoeger, T., Saber, A. T., & Vogel, U. (2020). Acute Phase Response as a Biological Mechanism-of-Action of (Nano)particle-Induced Cardiovascular Disease. Small, 16(21), e1907476. https://doi.org/10.1002/smll.201907476

NCBI. (2023). Acute phase response related genes. https://www.ncbi.nlm.nih.gov/gene/?term=acute+phase+response

Poulsen, S. S., Knudsen, K. B., Jackson, P., Weydahl, I. E., Saber, A. T., Wallin, H., & Vogel, U. (2017). Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice. PLoS One, 12(4), e0174167. https://doi.org/10.1371/journal.pone.0174167

Poulsen, S. S., Saber, A. T., Mortensen, A., Szarek, J., Wu, D., Williams, A., Andersen, O., Jacobsen, N. R., Yauk, C. L., Wallin, H., Halappanavar, S., & Vogel, U. (2015). Changes in cholesterol homeostasis and acute phase response link pulmonary exposure to multi-walled carbon nanotubes to risk of cardiovascular disease. Toxicol Appl Pharmacol, 283(3), 210–222. https://doi.org/10.1016/j.taap.2015.01.011

Poulsen, S. S., Saber, A. T., Williams, A., Andersen, O., Kobler, C., Atluri, R., Pozzebon, M. E., Mucelli, S. P., Simion, M., Rickerby, D., Mortensen, A., Jackson, P., Kyjovska, Z. O., Molhave, K., Jacobsen, N. R., Jensen, K. A., Yauk, C. L., Wallin, H., Halappanavar, S., & Vogel, U. (2015). MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol, 284(1), 16–32. https://doi.org/10.1016/j.taap.2014.12.011

Saber, A. T., Halappanavar, S., Folkmann, J. K., Bornholdt, J., Boisen, A. M., Moller, P., Williams, A., Yauk, C., Vogel, U., Loft, S., & Wallin, H. (2009). Lack of acute phase response in the livers of mice exposed to diesel exhaust particles or carbon black by inhalation. Part Fibre Toxicol, 6, 12. https://doi.org/10.1186/1743-8977-6-12

Saber, A. T., Jacobsen, N. R., Jackson, P., Poulsen, S. S., Kyjovska, Z. O., Halappanavar, S., Yauk, C. L., Wallin, H., & Vogel, U. (2014). Particle-induced pulmonary acute phase response may be the causal link between particle inhalation and cardiovascular disease. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 6(6), 517–531. https://doi.org/10.1002/wnan.1279

Saber, A. T., Lamson, J. S., Jacobsen, N. R., Ravn-Haren, G., Hougaard, K. S., Nyendi, A. N., Wahlberg, P., Madsen, A. M., Jackson, P., Wallin, H., & Vogel, U. (2013). Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk. PLoS One, 8(7), e69020. https://doi.org/10.1371/journal.pone.0069020

Uhlar, C. M., & Whitehead, A. S. (1999). Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem, 265(2), 501–523. https://doi.org/10.1046/j.1432-1327.1999.00657.x

Urieli-Shoval, S., Cohen, P., Eisenberg, S., & Matzner, Y. (1998). Widespread expression of serum amyloid A in histologically normal human tissues. Predominant localization to the epithelium. J Histochem Cytochem, 46(12), 1377–1384. https://doi.org/10.1177/002215549804601206

Van Eeden, S., Leipsic, J., Paul Man, S. F., & Sin, D. D. (2012). The relationship between lung inflammation and cardiovascular disease. Am J Respir Crit Care Med, 186(1), 11–16. https://doi.org/10.1164/rccm.201203-0455PP

Wallin, H., Kyjovska, Z. O., Poulsen, S. S., Jacobsen, N. R., Saber, A. T., Bengtson, S., Jackson, P., & Vogel, U. (2017). Surface modification does not influence the genotoxic and inflammatory effects of TiO2 nanoparticles after pulmonary exposure by instillation in mice. Mutagenesis, 32(1), 47–57. https://doi.org/10.1093/mutage/gew046