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Relationship: 3092

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, ROS leads to Decreased, PPAR-gamma activation

Upstream event

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

Increase, ROS

Downstream event

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

Decreased, PPAR-gamma activation

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
Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway	adjacent	High	Not Specified	John Frisch (send email)	Under development: Not open for comment. Do not cite

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	High	NCBI
rat	Rattus norvegicus	High	NCBI
mouse	Mus musculus	High	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	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

Oxidative stress occurs due to the accumulation of reactive oxygen species (ROS). ROS can damage DNA, lipids, and proteins (Shields et al. 2021). Superoxide dismutase is an enzyme in a common cellular defense pathway, in which superoxide dismutase converts superoxide radicals to hydrogen peroxide. When cellular defense mechanisms are unable to mitigate ROS formation from mitochondrial respiration and stressors (biological, chemical, radiation), one established pathway that is disrupted involves Peroxisome proliferation-activated receptors.

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

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Support for this KER is referenced in publications cited in the originating work of Jeong and Choi (2020).

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 linking decreases in Peroxisome proliferation-activated receptors to reactive oxygen species (ROS) is strong. Reactive oxygen species (ROS) are produced by many normal cellular processes (ex. cellular respiration, mitochondrial electron transport, specialized enzyme reactions) and occur in multiple chemical forms (ex. superoxide anion, hydroxyl radical, hydrogen peroxide). Antioxidant enzymes play a major role in reducing reactive oxygen species (ROS) levels in cells (Ray et al. 2012) to prevent cellular damage to lipids, proteins, and DNA (Juan et al. 2021). This Key Event Relationship focuses on the disruption of Peroxisome proliferation-activated receptors gene expression due to increases in Reactive oxygen species (ROS) level.

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	Duration	Dose	Increased ROS?	Decreased PPAR?	Summary	Citation
Lab rats (Rattus norvegicus)	4 weeks	Diet exposure of 10% D-glucose, with 1000 mg/kg feed alpha-lipoic acid supplement evaluated to mitigate D-glucose effects	Yes	Yes	Male rats showed increased superoxide levels in glucose treatment but not glucose plus alpha-lipoic acid treatment, and corresponding patterns in PPAR-gamma gene expression in the treatments.	El Midaoui et al. (2006)
Human (Homo sapiens) and cow (Bos taurus)	72 hours	In vitro exposure of 1-1000 uM hydrogen peroxide	Assumed	Yes	Human umbilical vein endothelial cells and bovine aortic endothelial cells showed increased dose-dependent cytotoxicity when was assumed to correlated with higher reactive oxygen species (ROS) levels, PPARgamma gene expression levels showed corresponding decreases.	Blanquicett et al. (2010)
Lab mice (Mus musculus)	5 weeks	Diet exposure of 100, 1000 ug/L of 0.5, 50 um polystyrene microplastics	Assumed	Yes	Study selected stressor(s) known to elevate reactive oxygen species (ROS) levels. Male mice showed decreased gene expression of Peroxisome proliferation-activated receptor (PPAR-gamma) in blood.	Lu et al. (2018)
Zebrafish (Danio rerio)	4 weeks	Diet exposure of rosiglitazone, mitigation with N-acetylcysteine, L-carnitine, cold and heat stress, fish with PPAR-gamma mutations	Yes	Yes	Male and female fish had increased ROS levels and corresponding decreases in PPAR-gamma expression levels	Wang et al. (2022)

1 Assumed: study selected stressor(s) known to elevate reactive oxygen species (ROS) levels, endpoints verified increased oxidative stress and disrupted pathway.

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

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

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

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

Life Stage: The life stage applicable to this key event relationship is all life stages.

Sex: This key event relationship applies to both males and females.

Taxonomic: This key event relationship appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats) and teleost fish.

References

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

Blanquicett, C., Kang, B-Y., Ritzenthaler, J.D. Jones, D.P., and Hart, C.M. 2010. Oxidative stress modulates PPARγ in vascular endothelial cells. Free Radical Biology and Medicine 48: 1618-1625.

El Midaoui, A., Wu, L., Wang, R., and de Champlain, J. 2006. Modulation of cardiac and aortic peroxisome proliferator-activated receptor-gamma expression by oxidative stress in chronically glucose-fed rats. American Journal of Hypertension 19: 407-412.

Juan, C.A., de la Lastra, J.M.P., Plou, F.J., and Lebena, E.P. 2021. The chemistry of reactive oxygen species (ROS) revisited: Outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. International Journal of Molecular Sciences 22: 4642.

Lu, L., Wan, Z., Luo, T., Fu, Z., and Jin, Y. 2018. Polystyrene microplastics induce microbiota dysbiosis and hepatic lipid metabolism disorder in mice. Science of the Total Environment 631-632: 449-458.

Ray, P.D., Huang, B.-W., and Tsuji, Y. 2012. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signalling. Cellular Signalling 24:981-990.