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Event: 2224

Key Event Title

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

Dysregulation of transcriptional expression within PPAR signaling network

Short name

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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
regulation of gene expression		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	High
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 dysregulation of PPAR mediated transcriptional expression within the PPAR signaling network following the binding of stressor ligands to the PPAR isoforms with either agonist or antagonist interactions. There is abundant evidence of showing how synthetic ligands can affect transcriptional expression in the PPAR signaling network and of key genes involved in lipid homeostasis (Meierhofer et al. 2014; Li et al. 2020; Cariello et al. 2021; Heintz et al. 2022; Eide et al. 2023; Heintz et al. 2024). Specifically, pathway and gene ontology (GO) enrichment analyses have identified lipid metabolism, lipid transport, fatty acid degradation, PPAR signaling pathway, and lipid homeostasis as being transcriptionally altered in response to PFOS exposure (Chen et al. 2014; Jacobsen et al. 2018; Rodríguez-Jorquera et al. 2018; Martinez et al. 2019; Christou et al. 2020; Dong et al. 2021; Lee et al. 2021; Mylroie et al. 2021; Beale et al. 2022; Davidsen et al. 2022; Haimbuagh et al. 2022; Wang et al. 2022; Mylroie et al. IN PREP).

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

Targeted gene expression assays along with “omic” tools such as transcriptomics or proteomics can be used to determine if known or suspected ligands of the PPAR isoforms disrupt gene expression in the PPAR pathway. There are abundant resources available describing methodologies to assess disruption of 1 or more of the PPAR isoform pathways (Meierhofer et al. 2014; Li et al. 2020; Cariello et al. 2021; Mylroie et al. 2021; Heintz et al. 2022; Eide et al. 2023; Heintz et al. 2024).

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

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.

Cariello, M., Piccinin, E. and Moschetta, A., 2021. Transcriptional regulation of metabolic pathways via lipid-sensing nuclear receptors PPARs, FXR, and LXR in NASH. Cellular and molecular gastroenterology and hepatology, 11(5), pp.1519-1539.

Chen, J., Tanguay, R.L., Tal, T.L., Gai, Z., Ma, X., Bai, C., Tilton, S.C., Jin, D., Yang, D., Huang, C. and Dong, Q., 2014. Early life perfluorooctanesulphonic acid (PFOS) exposure impairs zebrafish organogenesis. Aquatic toxicology, 150, pp.124-132.

Christou, M., Fraser, T.W., Berg, V., Ropstad, E. and Kamstra, J.H., 2020. Calcium signaling as a possible mechanism behind increased locomotor response in zebrafish larvae exposed to a human relevant persistent organic pollutant mixture or PFOS. Environmental Research, 187, p.109702.

Davidsen, N., Ramhøj, L., Lykkebo, C.A., Kugathas, I., Poulsen, R., Rosenmai, A.K., Evrard, B., Darde, T.A., Axelstad, M., Bahl, M.I. and Hansen, M., 2022. PFOS-induced thyroid hormone system disrupted rats display organ-specific changes in their transcriptomes. Environmental Pollution, 305, p.119340.

de la Rosa Rodriguez, M.A., Sugahara, G., Hooiveld, G.J., Ishida, Y., Tateno, C. and Kersten, S., 2018. The whole transcriptome effects of the PPARα agonist fenofibrate on livers of hepatocyte humanized mice. BMC genomics, 19, pp.1-16.

Dong, G., Zhang, R., Huang, H., Lu, C., Xia, Y., Wang, X. and Du, G., 2021. Exploration of the developmental toxicity of TCS and PFOS to zebrafish embryos by whole-genome gene expression analyses. Environmental Science and Pollution Research, 28(40), pp.56032-56042.

Eide, M., Goksøyr, A., Yadetie, F., Gilabert, A., Bartosova, Z., Frøysa, H.G., Fallahi, S., Zhang, X., Blaser, N., Jonassen, I. and Bruheim, P., 2023. Integrative omics-analysis of lipid metabolism regulation by peroxisome proliferator-activated receptor a and b agonists in male Atlantic cod. Frontiers in physiology, 14, p.1129089.

Haimbaugh, A., Wu, C.C., Akemann, C., Meyer, D.N., Connell, M., Abdi, M., Khalaf, A., Johnson, D. and Baker, T.R., 2022. Multi-and transgenerational effects of developmental exposure to environmental levels of PFAS and PFAS mixture in zebrafish (Danio rerio). Toxics, 10(6), p.334.

Heintz MM, Chappell GA, Thompson CM, Haws LC. Evaluation of transcriptomic responses in livers of mice exposed to the short-chain PFAS compound HFPO-DA. Frontiers in Toxicology. 2022 Jun 27;4:937168.

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.

Jacobsen, A.V., Nordén, M., Engwall, M. and Scherbak, N., 2018. Effects of perfluorooctane sulfonate on genes controlling hepatic fatty acid metabolism in livers of chicken embryos. Environmental Science and Pollution Research, 25, pp.23074-23081.

Lee, H., Sung, E.J., Seo, S., Min, E.K., Lee, J.Y., Shim, I., Kim, P., Kim, T.Y., Lee, S. and Kim, K.T., 2021. Integrated multi-omics analysis reveals the underlying molecular mechanism for developmental neurotoxicity of perfluorooctanesulfonic acid in zebrafish. Environment International, 157, p.106802.

Li, Y., Zhang, Q., Fang, J., Ma, N., Geng, X., Xu, M., Yang, H. and Jia, X., 2020. Hepatotoxicity study of combined exposure of DEHP and ethanol: A comprehensive analysis of transcriptomics and metabolomics. Food and chemical toxicology, 141, p.111370.

Martínez, R., Navarro-Martín, L., Luccarelli, C., Codina, A.E., Raldúa, D., Barata, C., Tauler, R. and Piña, B., 2019. Unravelling the mechanisms of PFOS toxicity by combining morphological and transcriptomic analyses in zebrafish embryos. Science of the Total Environment, 674, pp.462-471.

Meierhofer, D., Weidner, C. and Sauer, S., 2014. Integrative analysis of transcriptomics, proteomics, and metabolomics data of white adipose and liver tissue of high-fat diet and rosiglitazone-treated insulin-resistant mice identified pathway alterations and molecular hubs. Journal of proteome research, 13(12), pp.5592-5602.

Mylroie, J.E., Wilbanks, M.S., Kimble, A.N., To, K.T., Cox, C.S., McLeod, S.J., Gust, K.A., Moore, D.W., Perkins, E.J. and Garcia‐Reyero, N., 2021. Perfluorooctanesulfonic acid–induced toxicity on zebrafish embryos in the presence or absence of the chorion. Environmental toxicology and chemistry, 40(3), pp.780-791.

Mylroie, J.E., Gust, K.A., Kimble, A.N., Wilbanks, M.W., Steward, C., Chapman, K.A., Kennedy, A.L., Jensen, K., Erickson, R., Ankley G.T, Conder, J., Vinas, N.G., Moore, D.W., Histological and Transcriptomic Evidence of Disrupted Lipid Metabolism in a Three-Generation Exposure of the Zebrafish (Danio rerio) to Perfluorooctane Sulfonate (PFOS). IN PREP.

Rodríguez-Jorquera, I.A., Colli-Dula, R.C., Kroll, K., Jayasinghe, B.S., Parachu Marco, M.V., Silva-Sanchez, C., Toor, G.S. and Denslow, N.D., 2018. Blood transcriptomics analysis of fish exposed to perfluoro alkyls substances: assessment of a non-lethal sampling technique for advancing aquatic toxicology research. Environmental science & technology, 53(3), pp.1441-1452.

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