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Relationship: 3093

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

Decreased, PPAR-gamma activation leads to Alteration, lipid metabolism

Upstream event

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

Decreased, PPAR-gamma activation

Downstream event

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

Alteration, lipid metabolism

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 Do not cite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
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

Expression of Peroxisome proliferator-activated receptors (PPAR) family genes are closely related to different aspects of lipid metabolism, and resulting organism fat content. PPAR-alpha, PPAR-gamma, and PPAR-delta families of genes are most often discussed when considering lipid metabolism. PPAR-alpha family genes are linked to regulation of lipid metabolism, lipoprotein synthesis, and metabolism processes, while PPAR-gamma family genes are linked to the proliferation of adipose cells, and PPAR-delta family genes are linked to changes in metabolic response due to environmental change. In this Key Event Relationship, we focus on the effects of decreased expression of PPAR-gamma family genes, with altered lipid metabolism.

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 lipid metabolism is strong. Disruption of cellular processors via stressors have been shown to decrease PPAR-gamma gene expression, with corresponding decreases in lipid metabolism and/or increases in fat content of organisms.

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

For review see Berger et al. (2002), Luquet et al. (2005), Den Broder et al. (2015). Experiments cited here have been conducted with lab mammals and with fish.

Species	Duration	Dose	Decreased PPAR?	Alteration lipid metabolism?	Summary	Citation
Human (Homo sapiens) and lab mice (Mus musculus)	2 hours – 16 weeks	In vitro exposure of 10e-10M to 10e-5M dibutyltin and tributyltin and 500 nm rosiglitazone and diet exposure of 50, 500 nM dibutyltin and 50 nM tributyltin.	Yes	Yes	In human and mouse cells, as well as lab mice, increased activation of PPAR-gamma gene expression was correlated with increases in glucose levels and increased weight gain.	Chamorro-Garcia et al. (2018)
Zebrafish (Danio rerio)	3 days	Aquatic exposure of 10 μM Rosiglitazone, T0070907, GW6471, GW590735, GSK3787, or GW501516.	Yes	Yes	Embryos exposed to PPAR antagonist compounds had decreased PPAR-gamma gene expression correlated with decreased lipid accumulations, embryos exposed to PPAR agonist compounds had increased PPAR-gamma gene expression correlated with increased lipid accumulations.	Venezia et al. (2021)
Lab mice (Mus musculus)	5 weeks	Diet exposure of 100, 1000 ug/L of 0.5, 50 um polystyrene microplastics	Yes	Yes	Male mice showed decreased gene expression of Peroxisome proliferation-activated receptor (PPAR-gamma) correlated with decreased glucose levels and fat content.	Lu et al. (2018)

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

Berger, J. and Moller, D. 2002. The mechanisms of action of PPARS. Annual Review of Medicine 53: 409-435.

Chamorro-Garcia, R., Shoucri, B.M., Willner, S., Kach, H., Janesick, A., and Blumberg, B. 2018. Effect of perinatal exposure to dibutyltin chloride on fat and glucose metabolism in mice, and molecular mechanisms, in vitro. Environmental Health Perspectives 126(5): 057006.

Den Broeder, M.J., Kopylova, V.A., Kamminga, L.M. Legler, J. 2015. Zebrafish as a model to study the role of peroxisome proliferating-activated receptors in adipogenesis and obesity. PPAR Research 2015: 358029.

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.

Luquet, S., Gaudel, C., Holst, D., Lopez-Soriano, J., Jehl-Pietri, C., Fredenrich, A., and Grimaldi, P.A. 2005. Roles of PPAR delta in lipid absorption and metabolism: A new target for the treatment of type 2 diabetes. Biochimica and Biophysica Acta 1740: 313-317.

Venezia, O., Islam, S., Cho, C., Timme-Laragy, A.R., and Sant, K.E. 2021. Modulation of PPAR signaling disrupts pancreas development in the zebrafish, Danio rerio. Toxicology and Applied Pharmacology 426: 115653.