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Relationship: 3223

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 Decrease, Fatty acid β-oxidation

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

Decrease, Fatty acid β-oxidation

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 Do not cite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 β-oxidation and specifically cause a decrease in β-oxidation. All 3 PPAR isoforms and the genes they regulate are essential for proper energy homeostasis of which β-oxidation is a key component; and therefore, dysregulation in the expression profiles of any or all of the PPAR isoform controlled signaling networks can disrupt fatty acid β-oxidation in cells (Ament et al. 2012; Liu et al. 2020; 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 β-oxidation (Dixon et al. 2021; Xiao et al. 2021) as the PPAR isoforms play a key role in regulating β-oxidation (Cherkaoui-Malki et al. 2012). PPARα knockouts have shown decreased β-oxidation and subsequent lipid accumulation in the liver (Hashimoto et al. 2000; Reddy 2001; Badman et al. 2007) whereas activation of PPARα has been shown to increase β-oxidation (Tahri-Joutey et al. 2021). PPARβ/δ has also been shown to have a critical role in the regulation β-oxidation and PPARγ activation promotes lipid storage and decreases fatty acid β-oxidation (Reddy 2001; Roberts et al. 2011).

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 β-oxidation, PPAR signaling pathway, and lipid homeostasis as being transcriptionally altered in response to PFAS exposure (Chen et al. 2014; Tse et al. 2016; Cui et al. 2017; Huck et al. 2018; Jacobsen et al. 2018; Rodríguez-Jorquera et al. 2018; Liu et al. 2019; Martinez et al. 2019; Christou et al. 2020; Louisse 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).

The proper control of mitochondrial β -oxidation is reliant on PPAR induced transcription of the enzymes integral to carrying out fatty acid oxidation (Fan and Evans 2015; Hong et al. 2019). Agonist of PPARα increase gene expression of genes involved in mitochondrial fatty acid β -oxidation (Bougarne et al. 2018) whereas PPARα null mice have a decreased expression of fatty acid oxidation genes with the same being seen in PPARβ/δ knockouts (Wang 2010).

Stressors can impact the expression of genes involved in β -oxidation. For example, in mammal models, up-regulation of β -oxidation related genes Thiolase B and cyp4a1 have been observed in rats [Rattus norvegicus] (Davidsen et al. 2022) and with cyp4a14 and acadm observed as upregulated in mice (Rosen et al. 2010) after exposure to PFAS. At a cellular level, Wan et al. (2012) and Geng et al. (2019) demonstrated decreases in overall mitochondrial β -oxidation rates in liver tissue from PFOS exposed mice and chicken [Gallus gallus] embryos. In zebrafish, Cheng et al. (2016) observed increased transcriptional expression for genes related to β-oxidation (acox1, acadm, cpt1a) which is suggestive of a compensatory response to β-oxidation inhibition caused by PFOS exposure. Similarly, Wang et al. (2022) also observed trends of increased transcriptional expression of genes in the β -oxidation pathway in zebrafish after PFOS exposure, and Yi et al. (2019) observed increased transcriptional expression of genes within the β -oxidation pathway including acox1 and acadm in response to PFOS. However, other investigations using zebrafish have observed genes in the β -oxidation pathway having decreased expression or mixed profiles of both increased and decreased expression (Tu et al. 2019; Mylroie et al. 2021).

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. Finally, the fed state of the organism being assayed is important as food availability can have a direct effect on β-oxidation in the target organism.

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 and β-oxidation 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

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.

Badman, M.K., Pissios, P., Kennedy, A.R., Koukos, G., Flier, J.S. and Maratos-Flier, E., 2007. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell metabolism, 5(6), pp.426-437.

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.

Bougarne, N., Weyers, B., Desmet, S.J., Deckers, J., Ray, D.W., Staels, B. and De Bosscher, K., 2018. Molecular actions of PPAR α in lipid metabolism and inflammation. Endocrine reviews, 39(5), pp.760-802.

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.

Cherkaoui-Malki, M., Surapureddi, S., I El Hajj, H., Vamecq, J. and Andreoletti, P., 2012. Hepatic steatosis and peroxisomal fatty acid beta-oxidation. Current Drug Metabolism, 13(10), pp.1412-1421.

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.

Dixon, E.D., Nardo, A.D., Claudel, T. and Trauner, M., 2021. The role of lipid sensing nuclear receptors (PPARs and LXR) and metabolic lipases in obesity, diabetes and NAFLD. Genes, 12(5), p.645.

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.

Fan, W. and Evans, R., 2015. PPARs and ERRs: molecular mediators of mitochondrial metabolism. Current opinion in cell biology, 33, pp.49-54.

Geng, D., Musse, A.A., Wigh, V., Carlsson, C., Engwall, M., Orešič, M., Scherbak, N. and Hyötyläinen, T., 2019. Effect of perfluorooctanesulfonic acid (PFOS) on the liver lipid metabolism of the developing chicken embryo. Ecotoxicology and environmental safety, 170, pp.691-698.

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.

Hashimoto, T., Cook, W.S., Qi, C., Yeldandi, A.V., Reddy, J.K. and Rao, M.S., 2000. Defect in peroxisome proliferator-activated receptor α-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. Journal of Biological Chemistry, 275(37), pp.28918-28928.

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.

Hong, F., Pan, S., Guo, Y., Xu, P. and Zhai, Y., 2019. PPARs as nuclear receptors for nutrient and energy metabolism. Molecules, 24(14), p.2545.

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.

Liu, Z., Ding, J., McMillen, T.S., Villet, O., Tian, R. and Shao, D., 2020. Enhancing fatty acid oxidation negatively regulates PPARs signaling in the heart. Journal of molecular and cellular cardiology, 146, pp.1-11.

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.

Reddy, J.K., 2001. III. Peroxisomal β-oxidation, PPARα, and steatohepatitis. American Journal of Physiology-Gastrointestinal and Liver Physiology, 281(6), pp.G1333-G1339.

Roberts, L.D., Murray, A.J., Menassa, D., Ashmore, T., Nicholls, A.W. and Griffin, J.L., 2011. The contrasting roles of PPARδ and PPARγ in regulating the metabolic switch between oxidation and storage of fats in white adipose tissue. Genome biology, 12, pp.1-19.

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.

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.

Tu, W., Martinez, R., Navarro-Martin, L., Kostyniuk, D.J., Hum, C., Huang, J., Deng, M., Jin, Y., Chan, H.M. and Mennigen, J.A., 2019. Bioconcentration and metabolic effects of emerging PFOS alternatives in developing zebrafish. Environmental Science & Technology, 53(22), pp.13427-13439.

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, Y.X., 2010. PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell research, 20(2), pp.124-137.

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.