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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 APP leads to Systemic APR

Upstream event

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

Increased transcription of genes encoding APP

Downstream event

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

Systemic APR

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 Do not cite	Under Development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 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

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

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 ¹. These proteins are then release to the systemic circulation ².

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

Species	Stressor	Acute phase protein expression	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 SAA at 1 and 28 days after exposure.	³
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.	^4,5
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.	^4,5
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.	⁶
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 SAA3 plasma concentration 3 days after exposure.	⁶
Mouse	Multiwalled carbon nanotubes (NM-400 to NM-403)	Yes, increased Saa1 mRNA expression in liver tissue with all MWCNTs, 1 day after exposure to 54 µg, and after exposure to 18 µg in the case of NM-401 and NM-403. After 28 days, only NM-400 (54 µg) produced an increase in Saa1 mRNA levels in liver tissue. Increased Saa3 mRNA expression in lung tissue with all MWCNTs, 1 day after exposure to 54 µg, and after exposure to 6 and 18 µg in the case of NM-402 and NM-403. After 28 days, NM-400 (18 and 54), NM-402 (54 µg) and NM-403 (54 µg) produced an increase in Saa3 mRNA levels in lung tissue.	Yes, increased SAA1/2 plasma levels 1 day after exposure to NM-400, NM-401 and NM-403. No change in SAA1/2 28 and 92 days after exposure. Increased SAA3 plasma levels 1 days after exposure to all MWCNT. Increased SAA3 plasma levels 28 and 92 days after exposure to NM-401.	⁷
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.	⁸
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.	⁸
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.	⁸
Mouse	Carbon black	Yes, increased expression of Saa3 mRNA in lung tissue at day 1 and day 90.	No change in plasma SAA3.	⁸
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.	⁹
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.	⁹
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.	¹⁰
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.	¹⁰
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.	¹⁰
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.	¹⁰
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.	¹⁰
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.	¹¹
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.	¹¹
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 SAA3.	¹²

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 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

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

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.

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 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

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 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.

References

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

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).