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Event: 2226

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Stressor binding PPAR isoforms

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Binding PPAR isoforms

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
eukaryotic cell

Organ term

Organ term
liver

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
receptor binding		occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
PFOS binding to PPARs leads to liver steatosis	MolecularInitiatingEvent	Evgeniia Kazymova (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	High	NCBI

Life Stages

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

Life stage	Evidence
Embryo	Moderate
Juvenile	High
Adult, reproductively mature	High

Sex Applicability

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

Term	Evidence
Male	High
Female	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Both natural and synthetic ligands can interact with all 3 main PPAR isoforms with unsaturated fatty acids and other lipid-derived molecules being the primary natural ligands the PPAR isoforms (Ferré 2004). This Key Event describes the binding of stressor ligands to the PPAR isoforms with either agonist or antagonist interactions. Numerous studies have shown the ability of synthetic ligands to bind the ligand binding domains of the PPAR isoforms (α, β/δ, γ). Some of these synthetic ligands can be PPAR isoform specific whereas others, like bezafibrate, can bind and activate all 3 main PPAR isoforms (Grygiel-Górniak 2014). Specifically, the prototypical stressor, PFOS, has been shown to bind the three PPAR isoforms with varying degrees of affinity through in vitro ligand binding assays (Vanden Heuvel et al. 2006; Takacs and Abbot 2007; Wolf et al. 2008; Behr et al. 2020; Evans et al. 2022; Sun et al. 2023) as well as through computational binding/docking analyses (Li et al. 2018; Yi et al. 2019; Almedia et al. 2021; Garoche et al. 2021; Khazee et al. 2021; Huang et al. 2022b; Wang et al. 2022a, Wang et al. 2022b; Kowalska et al. 2023).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Nuclear signaling assays, affinity assays, x-ray crystallography, and in silico analyses can all be used to assess the affinity and location of binding by known or potential ligands to the PPAR isoforms (Vanden Heuvel et al. 2006; Takacs and Abbot 2007; Capelli et al. 2016; Rajapaksha et al. 2017; Li et al. 2018; Behr et al. 2020; Almedia et al. 2021; Garoche et al. 2021; Evans et al. 2022; Sun et al. 2023). In silico analyses are a powerful screening tool to determine if a molecule of interest may be able to bind to one or more of the PPAR isoforms; however, confirmation of binding location should be done via x-ray crystallography. Nuclear signaling assays can be used to determine if a potential ligand of interest acts as an agonists or antagonists. A comprehensive example of in silico primary analyses coupled with confirmation steps using cell-based report assays and x-ray crystallography for PPAR isoforms can be found in Capelli et al. (2016).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

The conservation of PPAR molecular structure and function among vertebrates (Gust et al 2020) indicates this key event is likely to be conserved among this broad phylogenetic group. Furthermore, PPAR isoforms play a crucial role in lipid metabolism across representative vertebrate species. However, given that species to species variation does exist in structure and specific function, it is important to exercise care when looking to extrapolate across species.

References

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

Almeida, N.M., Eken, Y. and Wilson, A.K., 2021. Binding of per-and polyfluoro-alkyl substances to peroxisome proliferator-activated receptor gamma. ACS omega, 6(23), pp.15103-15114.

Behr, A.C., Plinsch, C., Braeuning, A. and Buhrke, T., 2020. Activation of human nuclear receptors by perfluoroalkylated substances (PFAS). Toxicology in Vitro, 62, p.104700.

Capelli, D., Cerchia, C., Montanari, R., Loiodice, F., Tortorella, P., Laghezza, A., Cervoni, L., Pochetti, G. and Lavecchia, A., 2016. Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode. Scientific reports, 6(1), p.34792.

Evans, N., Conley, J.M., Cardon, M., Hartig, P., Medlock-Kakaley, E. and Gray Jr, L.E., 2022. In vitro activity of a panel of per-and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays. Toxicology and Applied Pharmacology, 449, p.116136.

Ferré, P., 2004. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes, 53(suppl_1), pp.S43-S50.

Garoche, C., Boulahtouf, A., Grimaldi, M., Chiavarina, B., Toporova, L., den Broeder, M.J., Legler, J., Bourguet, W. and Balaguer, P., 2021. Interspecies Differences in Activation of Peroxisome Proliferator-Activated Receptor γ by Pharmaceutical and Environmental Chemicals. Environmental Science & Technology, 55(24), pp.16489-16501.

Grygiel-Górniak, B., 2014. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications-a review. Nutrition journal, 13, pp.1-10.

Gust, K.A., Ji, Q., Luo, X., 2020. Example of Adverse Outcome Pathway Concept Enabling Genome-to-Phenome Discovery in Toxicology. Integr. Comp. Biol. 60, 375-384.

Huang, J., Wang, Q., Liu, S., Lai, H. and Tu, W., 2022. Comparative chronic toxicities of PFOS and its novel alternatives on the immune system associated with intestinal microbiota dysbiosis in adult zebrafish. Journal of Hazardous Materials, 425, p.127950.

Khazaee, M., Christie, E., Cheng, W., Michalsen, M., Field, J. and Ng, C., 2021. Perfluoroalkyl acid binding with peroxisome proliferator-activated receptors α, γ, and δ, and fatty acid binding proteins by equilibrium dialysis with a comparison of methods. Toxics, 9(3), p.45.

Kowalska, D., Sosnowska, A., Bulawska, N., Stępnik, M., Besselink, H., Behnisch, P. and Puzyn, T., 2023. How the Structure of Per-and Polyfluoroalkyl Substances (PFAS) Influences Their Binding Potency to the Peroxisome Proliferator-Activated and Thyroid Hormone Receptors—An In Silico Screening Study. Molecules, 28(2), p.479.

Li, C.H., Ren, X.M., Ruan, T., Cao, L.Y., Xin, Y., Guo, L.H. and Jiang, G., 2018. Chlorinated polyfluorinated ether sulfonates exhibit higher activity toward peroxisome proliferator-activated receptors signaling pathways than perfluorooctanesulfonate. Environmental science & technology, 52(5), pp.3232-3239.

Rajapaksha, H., Bhatia, H., Wegener, K., Petrovsky, N. and Bruning, J.B., 2017. X-ray crystal structure of rivoglitazone bound to PPARγ and PPAR subtype selectivity of TZDs. Biochimica et Biophysica Acta (BBA)-General Subjects, 1861(8), pp.1981-1991.

Sun, X., Xie, Y., Zhang, X., Song, J. and Wu, Y., 2023. Estimation of Per-and Polyfluorinated Alkyl Substance Induction Equivalency Factors for Humpback Dolphins by Transactivation Potencies of Peroxisome Proliferator-Activated Receptors. Environmental Science & Technology, 57(9), pp.3713-3721.

Takacs, M.L. and Abbott, B.D., 2007. Activation of mouse and human peroxisome proliferator–activated receptors (α, β/δ, γ) by perfluorooctanoic acid and perfluorooctane sulfonate. Toxicological Sciences, 95(1), pp.108-117.

Vanden Heuvel, J.P., Thompson, J.T., Frame, S.R. and Gillies, P.J., 2006. Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-α,-β, and-γ, liver X receptor-β, and retinoid X receptor-α. Toxicological Sciences, 92(2), pp.476-489.

Wang, Q., Huang, J., Liu, S., Wang, C., Jin, Y., Lai, H. and Tu, W., 2022a. Aberrant hepatic lipid metabolism associated with gut microbiota dysbiosis triggers hepatotoxicity of novel PFOS alternatives in adult zebrafish. Environment International, 166, p.107351.

Wang, P., Liu, D., Yan, S., Cui, J., Liang, Y. and Ren, S., 2022b. Adverse effects of perfluorooctane sulfonate on the liver and relevant mechanisms. Toxics, 10(5), p.265.

Wolf, C.J., Takacs, M.L., Schmid, J.E., Lau, C. and Abbott, B.D., 2008. Activation of mouse and human peroxisome proliferator− activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths. Toxicological Sciences, 106(1), pp.162-171.

Yi, S., Chen, P., Yang, L. and Zhu, L., 2019. Probing the hepatotoxicity mechanisms of novel chlorinated polyfluoroalkyl sulfonates to zebrafish larvae: Implication of structural specificity. Environment international, 133, p.105262.