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Relationship: 3220

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

Binding PPAR isoforms leads to Disrupted PPAR isoform nuclear signaling

Upstream event

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

Binding PPAR isoforms

Downstream event

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

Disrupted PPAR isoform nuclear signaling

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
Xenobiotic binding to peroxisome proliferator-activated receptors (PPARs) causes dysregulation of lipid metabolism leading to liver steatosis	adjacent	High	Moderate	Erik Mylroie (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 Do not cite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
Vertebrates	Vertebrates	High	NCBI

Sex Applicability

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

Sex	Evidence
Male	High
Female	Moderate

Life Stage Applicability

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

Term	Evidence
Embryo	Moderate
Juvenile	High
Adult, reproductively mature	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

Both natural and synthetic ligands can interact with all 3 main PPAR isoforms (α, β/δ, γ) with unsaturated fatty acids and other lipid-derived molecules being the primary natural ligands the PPAR isoforms (Ferré 2004). Numerous studies have shown the ability of synthetic ligands to bind the ligand binding domains of the PPAR isoforms (Ferré 2004; Grygiel-Górniak 2014). This Key Event Relationship describes the binding of stressor ligands to the PPAR isoforms with either agonist or antagonist interactions which then disrupts downstream PPAR isoform nuclear signaling. The ligands that bind the PPAR isoforms either agonistically or antagonistically can disrupt proper PPAR activity and nuclear signaling for the either expression or repression of target genes.

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

Natural and synthetic ligands can interact with all 3 main PPAR isoforms (α, β/δ, γ) with unsaturated fatty acids and other lipid-derived molecules being the primary natural ligands the PPAR isoforms (Ferré 2004). Following binding with an activating ligand, PPAR isoforms heterodimerize with the retinoid X receptor (RXR) with this complex then recognizing the peroxisome proliferator response elements (PPRE) of the PPAR isoform target genes and promoting gene expression (Capelli et al. 2016). Therefore, ligands that act either agonistically or antagonistically beyond or more persistently than the normal biological range can disrupt proper nuclear signaling and subsequent gene expression.

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

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. 2022; Wang et al. 2022a, Wang et al. 2022b; Kowalska et al. 2023).

Results from activity assays, nuclear signaling assays, and transcriptomic analyses using PPAR isoform agonist and antagonist have demonstrate that PPAR ligands directly affect PPAR activity, nuclear signaling, and the transcription of PPAR mediated target genes (Kojo et al. 2003; Behr et al. 2020; Gao et al. 2020; Evans et al. 2022; Murase et al. 2023; Ardenkjær-Skinnerup et al. 2024). Moreover, studies have demonstrated that exposure to the prototypical stressor, PFOS, can have a direct effect on the transcriptional expression of the PPAR isoforms in vertebrates (Lee et al. 2020; Beale et al. 2022) with these studies showing expression changes occurring primarily in the PPARα and PPARγ isoforms.

Beyond the direct effects of stressor ligands on PPAR isoforms, activation of one PPAR isoform can have effects on the expression of other PPAR isoforms. For example, agonism of PPARβ/δ can cause reduced expression of PPARα and PPARγ isoforms (Shi et al. 2002; Kim et al. 2020; Kim et al. 2023), and certain coregulators can have effects (sometimes opposite) on different PPAR isoforms (Tahri-Joutey et al. 2021). Finally, omics studies have shown that agonist and antagonist of PPAR isoforms alter PPAR signaling transcripts (Louisse et al. 2020; Heintz et al. 2024). Overall, this evidence displays that disruption of PPAR isoforms via stressor chemicals can affect other PPAR isoforms and impact PPAR nuclear signaling.

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

While the PPAR molecular structure and function among vertebrates is largely conserved (Gust et al 2020), species to species variation does exist in structure and specific function; and therefore, it is important to exercise care when looking to extrapolate across species. The binding affinity of certain ligands and the magnintude of response in PPAR nuclear signaling may differ from species to species due to variations in PPAR molecular structure.

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

Unknown.

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

Rapid Molecular Interactions.

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

As PPAR signaling is essential for maintaining energy homeostasis, there is a complex network of feedforward/feedback loops influencing PPAR nuclear signaling via ligands, products, and the PPAR isoforms acting on each other. Due to extensive detail needed to properly describe all potential feedforward/feedback loops that could influence this KER, the authors direct readers to reviews by Ament et al. (2012) and Lamichane et al. (2018).

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

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 KER 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.

Ament, Z., Masoodi, M. and Griffin, J.L., 2012. Applications of metabolomics for understanding the action of peroxisome proliferator-activated receptors (PPARs) in diabetes, obesity and cancer. Genome Medicine, 4, pp.1-12.

Ardenkjær-Skinnerup, J., Nissen, A.C.V.E., Nikolov, N.G., Hadrup, N., Ravn-Haren, G., Wedebye, E.B. and Vogel, U., 2024. Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay. Environmental Toxicology and Pharmacology, 105, p.104347.

Beale, D.J., Sinclair, G., Shah, R., Paten, A., Kumar, A., Long, S.M., Vardy, S. and Jones, O.A., 2022. A review of omics-based PFAS exposure studies reveals common biochemical response pathways. Science of The Total Environment, p.157255.

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.

Gao, P., Wang, L., Yang, N., Wen, J., Zhao, M., Su, G., Zhang, J. and Weng, D., 2020. Peroxisome proliferator-activated receptor gamma (PPARγ) activation and metabolism disturbance induced by bisphenol A and its replacement analog bisphenol S using in vitro macrophages and in vivo mouse models. Environment international, 134, p.105328.

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.

Heintz, M.M., Klaren, W.D., East, A.W., Haws, L.C., McGreal, S.R., Campbell, R.R. and Thompson, C.M., 2024. Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in mouse, rat, and pooled human hepatocytes. Toxicological Sciences, p.kfae044.

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.

Kim, D.H., Kim, D.H., Heck, B.E., Shaffer, M., Yoo, K.H. and Hur, J., 2020. PPAR-δ agonist affects adipo-chondrogenic differentiation of human mesenchymal stem cells through the expression of PPAR-γ. Regenerative Therapy, 15, pp.103-111.

Kim, I.S., Silwal, P. and Jo, E.K., 2023. Peroxisome proliferator-activated receptor-targeted therapies: challenges upon infectious diseases. Cells, 12(4), p.650.

Kojo, H., Fukagawa, M., Tajima, K., Suzuki, A., Fujimura, T., Aramori, I., Hayashi, K.I. and Nishimura, S., 2003. Evaluation of human peroxisome proliferator-activated receptor (PPAR) subtype selectivity of a variety of anti-inflammatory drugs based on a novel assay for PPARδ (β). Journal of pharmacological sciences, 93(3), pp.347-355.

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.

Lamichane, S., Dahal Lamichane, B. and Kwon, S.M., 2018. Pivotal roles of peroxisome proliferator-activated receptors (PPARs) and their signal cascade for cellular and whole-body energy homeostasis. International journal of molecular sciences, 19(4), p.949.

Lee, J.W., Choi, K., Park, K., Seong, C., Do Yu, S. and Kim, P., 2020. Adverse effects of perfluoroalkyl acids on fish and other aquatic organisms: A review. Science of the Total Environment, 707, p.135334.

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.

Li, Y., Liu, X., Niu, L. and Li, Q., 2017. Proteomics analysis reveals an important role for the PPAR signaling pathway in DBDCT-induced hepatotoxicity mechanisms. Molecules, 22(7), p.1113.

Louisse, J., Rijkers, D., Stoopen, G., Janssen, A., Staats, M., Hoogenboom, R., Kersten, S. and Peijnenburg, A., 2020. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorononanoic acid (PFNA) increase triglyceride levels and decrease cholesterogenic gene expression in human HepaRG liver cells. Archives of toxicology, 94(9), pp.3137-3155.

Murase, W., Kubota, A., Ikeda-Araki, A., Terasaki, M., Nakagawa, K., Shizu, R., Yoshinari, K. and Kojima, H., 2023. Effects of perfluorooctanoic acid (PFOA) on gene expression profiles via nuclear receptors in HepaRG cells: Comparative study with in vitro transactivation assays. Toxicology, 494, p.153577.

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.

Shi, Y., Hon, M. and Evans, R.M., 2002. The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling. Proceedings of the National Academy of Sciences, 99(5), pp.2613-2618.

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.

Tahri-Joutey, M., Andreoletti, P., Surapureddi, S., Nasser, B., Cherkaoui-Malki, M. and Latruffe, N., 2021. Mechanisms mediating the regulation of peroxisomal fatty acid beta-oxidation by PPARα. International journal of molecular sciences, 22(16), p.8969.

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.