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Relationship: 3224

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

Dysregulation of transcriptional expression within PPAR signaling network leads to Disrupted Lipid Storage

Upstream event

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

Dysregulation of transcriptional expression within PPAR signaling network

Downstream event

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

Disrupted Lipid Storage

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 Do not cite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

This Key Event Relationship describes how the dysregulation of transcriptional expression within the PPAR signaling network results in disrupted lipid storage, specifically in liver cells. All 3 PPAR isoforms and the genes they regulate are essential for proper lipid storage and transport; and therefore, dysregulation in the expression profiles of any or all of the PPAR isoform controlled signaling networks can disrupt the proper storage of lipids in cells (Ament et al. 2012; Dixon et al. 2021; Xiao et al. 2021).

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

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 in the PPAR signaling pathway. The complex control of lipid metabolism means dysregulation of gene expression in the PPAR signaling network can have a disruptive effect on lipid storage and transport as all 3 PPAR isoforms and the genes they modulate play essential roles in the delicate control of lipid homeostasis (Dixon et al. 2021; Xiao et al. 2021).

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

Dysregulation of gene expression follows disrupted nuclear signaling as can be seen from 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).

When a stressor ligand binds to the PPAR isoforms with either agonist or antagonist interactions which can lead to effects on lipid storage and transport (Dixon et al. 2021). PPARγ over expression results in promotes storage of lipids in the liver and thus exacerbates hepatic steatosis (Yu et al. 2003; Patsouris et al. 2006). Conversely, deletion of PPARα resulted in an increased liver lipid (Patsouris et al. 2006). Wang et al. (2003) demonstrated that PPARβ/δ deficient mice had increased obesity which, while potentially not a function of improper lipid storage, underpins the importance of all PPAR isoforms in proper lipid homeostasis. Evidence of disruption of lipogenesis at the transcriptional level has also been observed across multiple studies using PFAS as the stressor (Tse et al. 2016; Cui et al. 2017; Huck et al. 2018; Liu et al. 2019; Martinez 2019; Yi et al. 2019; Louisse et al. 2020; Wang et al. 2022). Changes in lipogenesis could result in an accumulation of lipids in liver cells if lipogenesis is increased or transport is perturbed. Huck et al. (2018) saw a decrease expression in apoa1 and apoa2 in mice which has been associated with increased risk of liver steatosis (Karavia et al. 2012). Liu et al. (2019) and Louisse et al. (2020) saw an increase in expression in perilipin (Plin) family genes in human liver and stem cells exposed to PFOS, but Rodríguez-Jorquera et al. (2018) saw a decrease in Plin expression in livers from exposed fathead minnows. Plin family genes are involved in the formation and degradation of lipid droplets and thus dysregulation of these genes may impact proper lipid storage in the liver (Carr and Ahima 2016). Tse et al. (2016) saw an increase in apoe expression in zebrafish, which can signal a shift towards accumulation of lipids in hepatocytes. Furthermore, Wang et al. (2022) saw a trend of decreased transcriptional expression of genes involved in lipid synthesis in zebrafish in response to PFOS; whereas Yi et al. (2019) saw PFOS exposure result in an increase in acacb transcriptional expression, a gene involved in fatty acid synthesis.

Disruption in lipid transport in and out of liver cells can result in excess lipid accumulation in cells which can ultimately lead to liver steatosis. Specifically, previous work has shown that along with disruptions to β-oxidation and lipogenesis, PFOS exposure can result in transcriptional changes to lipid transport genes in terrestrial vertebrates and fish (Cheng et al. 2016; Tse et al. 2016; Cui et al. 2017; Rodríguez-Jorquera et al. 2018; Sant et al. 2018; Martinez 2019; Christou et al. 2020; Mylroie et al. 2021; Davidsen et al. 2022; Wang et al. 2022). Studies in mice (Huck et al. 2018; Liu et al. 2019), rats (Davidsen et al. 2022), and human cells (Wan et al. 2012), showed increases in CD36 expression in response to PFOS exposure. CD36 is responsible for transport of lipids in liver cells and an increase in CD36 expression due to PFOS exposure has been linked in increased TG levels in the liver (Jai et al. 2023). Dysregulation in fabp isoforms, which are responsible for the transport of fatty acids for fates such as β-oxidation and lipogenesis, was observed in mammals and fish exposed to PFOS (Rosen et al. 2010; Jacobsen et al. 2018; Sant et al. 2018; Mylroie et al. 2021; Wang et al. 2022). Furthermore, lpl, which is involved in the proper transport of triglycerides was shown to be upregulated in studies in human cells (Wan et al. 2012) and mice (Liu et al. 2019); conversely Cheng et al. (2016) and Tse et al. (2016) showed lpl to be downregulated in response to PFOS exposure in zebrafish. Finally, Rodríguez-Jorquera et al. (2018) saw an overall decrease in lipid transport related genes in livers from PFOS exposed fathead minnow.

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 magnitude of response in PPAR nuclear signaling may differ from species to species due to variations in PPAR molecular structure. Furthermore, the direction and magnitude of gene expression response may differ from species to species or even within species depending on the ligand assayed and the concentration used.

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 and gene expression via ligands, products, and the PPAR isoforms acting on each other. Due to the 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

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.

Carr, R.M. and Ahima, R.S., 2016. Pathophysiology of lipid droplet proteins in liver diseases. Experimental cell research, 340(2), pp.187-192.

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.

Cheng, J., Lv, S., Nie, S., Liu, J., Tong, S., Kang, N., Xiao, Y., Dong, Q., Huang, C. and Yang, D., 2016. Chronic perfluorooctane sulfonate (PFOS) exposure induces hepatic steatosis in zebrafish. Aquatic toxicology, 176, pp.45-52.

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.

Jia, Y., Zhu, Y., Wang, R., Ye, Q., Xu, D., Zhang, W., Zhang, Y., Shan, G. and Zhu, L., 2023. Novel insights into the mediating roles of cluster of differentiation 36 in transmembrane transport and tissue partition of per-and polyfluoroalkyl substances in mice. Journal of Hazardous Materials, 442, p.130129.

Karavia, E.A., Papachristou, D.J., Liopeta, K., Triantaphyllidou, I.E., Dimitrakopoulos, O. and Kypreos, K.E., 2012. Apolipoprotein AI modulates processes associated with diet-induced nonalcoholic fatty liver disease in mice. Molecular Medicine, 18(6), pp.901-912.

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.

Liu, S., Yang, R., Yin, N., Wang, Y.L. and Faiola, F., 2019. Environmental and human relevant PFOS and PFOA doses alter human mesenchymal stem cell self-renewal, adipogenesis and osteogenesis. Ecotoxicology and environmental safety, 169, pp.564-572.

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.

Rosen, M.B., Schmid, J.R., Corton, J.C., Zehr, R.D., Das, K.P., Abbott, B.D. and Lau, C., 2010. Gene expression profiling in wild-type and PPARα-null mice exposed to perfluorooctane sulfonate reveals PPARα-independent effects. PPAR research, 2010.

Sant, K.E., Sinno, P.P., Jacobs, H.M. and Timme-Laragy, A.R., 2018. Nrf2a modulates the embryonic antioxidant response to perfluorooctanesulfonic acid (PFOS) in the zebrafish, Danio rerio. Aquatic toxicology, 198, pp.92-102.

Wan, H.T., Zhao, Y.G., Wei, X., Hui, K.Y., Giesy, J.P. and Wong, C.K., 2012. PFOS-induced hepatic steatosis, the mechanistic actions on β-oxidation and lipid transport. Biochimica et Biophysica Acta (BBA)-General Subjects, 1820(7), pp.1092-1101.

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.

Xiao, Y., Kim, M. and Lazar, M.A., 2021. Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Molecular Metabolism, 50, p.101119.

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.