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Increased transcription of genes encoding APP leads to Systemic APR
Key Event Relationship Overview
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 Do not cite||Under Development|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
This KER presents the association between the transcription of acute phase protein genes in different tissues and induction of systemic acute phase response. The evidence of the KER presented is based on animal studies (mice).
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility is high. After gene expression of acute phase proteins in tissues during inflammatory conditions, mRNA is translated and folded into proteins 1. These proteins are then release to the systemic circulation 2.
Uncertainties and Inconsistencies
Although it is suggested that acute phase proteins are mainly produced in the liver 13, 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, while it is in the lung where there is a marked expression of Saa3 mRNA 14,15.
It has been observed in some studies that the increase of Saa genes in lung or liver tissue does not translate into an increase in plasma SAA concentration 6,8,9. This might be due to a protein concentration below the methods detection levels9, while measuring gene expression provides a larger dynamic range.
Known modulating factors
A Pearson’s correlation coefficient of 0.89 (p<0.001) has been calculated between log-transformed Saa3 mRNA levels in lung tissue and log-transformed SAA3 plasma protein levels, in female C57BL/6J mice 1 day after intratracheal instillation of metal oxide nanomaterials 10 (Figure 1).
Figure 1. Correlations between Saa3 mRNA levels in lung tissue and SAA3 plasma protein levels, including data from 1 day after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023)10.
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 day after exposure 16.
After exposure to multiwalled carbonanotubes, 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 7.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Acute phase response is present in vertebrate species 17. In addition, serum amyloid A, one of the major acute phase proteins, has been conserved in mammals throughout evolution and has been described in humans, mice, dogs, horses, among others 18.
1 Alberts, B. Molecular biology of the cell. Sixth edition. edn, (CRC Press, an imprint of Garland Science, 2017).
2 Van Eeden, S., Leipsic, J., Paul Man, S. F. & Sin, D. D. The relationship between lung inflammation and cardiovascular disease. Am J Respir Crit Care Med 186, 11-16, doi:10.1164/rccm.201203-0455PP (2012).
3 Bourdon, J. A. et al. 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, 474-484, doi:10.1093/toxsci/kfs119 (2012).
4 Poulsen, S. S. et al. 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, 210-222, doi:10.1016/j.taap.2015.01.011 (2015).
5 Poulsen, S. S. et al. 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, 16-32, doi:10.1016/j.taap.2014.12.011 (2015).
6 Bengtson, S. et al. 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, e0178355, doi:10.1371/journal.pone.0178355 (2017).
7 Poulsen, S. S. et al. Multi-walled carbon nanotube-physicochemical properties predict the systemic acute phase response following pulmonary exposure in mice. PLoS One 12, e0174167, doi:10.1371/journal.pone.0174167 (2017).
8 Bendtsen, K. M. et al. Airport emission particles: exposure characterization and toxicity following intratracheal instillation in mice. Part Fibre Toxicol 16, 23, doi:10.1186/s12989-019-0305-5 (2019).
9 Hadrup, N. et al. Acute phase response and inflammation following pulmonary exposure to low doses of zinc oxide nanoparticles in mice. Nanotoxicology 13, 1275-1292, doi:10.1080/17435390.2019.1654004 (2019).
10 Gutierrez, C. T. et al. Acute phase response following pulmonary exposure to soluble and insoluble metal oxide nanomaterials in mice. Part Fibre Toxicol 20, 4, doi:10.1186/s12989-023-00514-0 (2023).
11 Erdely, A. et al. Identification of systemic markers from a pulmonary carbon nanotube exposure. J Occup Environ Med 53, S80-86, doi:10.1097/JOM.0b013e31821ad724 (2011).
12 Christophersen, D. V. et al. Accelerated atherosclerosis caused by serum amyloid A response in lungs of ApoE(-/-) mice. FASEB J 35, e21307, doi:10.1096/fj.202002017R (2021).
13 Gabay, C. & Kushner, I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340, 448-454, doi:10.1056/NEJM199902113400607 (1999).
14 Saber, A. T. et al. 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, doi:10.1186/1743-8977-6-12 (2009).
15 Saber, A. T. et al. Particle-induced pulmonary acute phase response correlates with neutrophil influx linking inhaled particles and cardiovascular risk. PLoS One 8, e69020, doi:10.1371/journal.pone.0069020 (2013).
16 Wallin, H. et al. Surface modification does not influence the genotoxic and inflammatory effects of TiO2 nanoparticles after pulmonary exposure by instillation in mice. Mutagenesis 32, 47-57, doi:10.1093/mutage/gew046 (2017).
17 Cray, C., Zaias, J. & Altman, N. H. Acute phase response in animals: a review. Comp Med 59, 517-526 (2009).
18 Uhlar, C. M. & Whitehead, A. S. Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265, 501-523, doi:10.1046/j.1432-1327.1999.00657.x (1999).