This Event is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Event: 2227

Key Event Title

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

Disrupted PPAR isoform nuclear signaling

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

Explore in a Third Party Tool

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
peroxisome proliferator activated receptor signaling pathway		disrupted

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	KeyEvent	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 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

This Key Event describes disruption of PPAR isoform nuclear signaling following the binding of stressor ligands to the PPAR isoforms with either agonist or antagonist interactions. 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 promoting gene expression (Capelli et al. 2016). Therefore, non-native ligands that bind the PPAR isoforms either agonistically or antagonistically can disrupt proper PPAR activity and signaling of either expression or repression of target genes. 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), 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.

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

Activity assays, nuclear signaling assays, and transcriptomic or proteomic analyses can identify disrupted nuclear signaling as the result of ligand binding to PPAR isoforms (Kojo et al. 2003; Li et al. 2017; Gao et al. 2020; Murase et al. 2023; Ardenkjær-Skinnerup et al. 2024). These assays can be used to determine if a potential ligand of interest acts as an agonists or antagonists either via direct activity assays or by analysis of gene targets in the PPAR isoform pathways.

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

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.

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.

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.

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.

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.

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, 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.

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.

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.