The DOI matches its Crossref record; 72 of the 72 references it cites were found in a registry or an index.
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
Open accessAbstract
Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We utilized in vitro assays with either human or rat PPARα or PPARγ ligand binding domains to evaluate 16 PFAS (HFPO-DA, HFPO-DA-AS, NBP2, PFMOAA, PFHxA, PFOA, PFNA, PFDA, PFOS, PFBS, PFHxS, PFOSA, EtPFOSA, and 4:2, 6:2 and 8:2 FTOH), 3 endogenous fatty acids (oleic, linoleic, and octanoic), and 3 pharmaceuticals (WY14643, clofibrate, and the metabolite clofibric acid). We also tested chemicals for human estrogen receptor (hER) transcriptional activation. Nearly all compounds activated both PPARα and PPARγ in both human and rat ligand binding domain assays, except for the FTOH compounds and PFOSA. Receptor activation and relative potencies were evaluated based on effect concentration 20% (EC 20), top percent of max fold induction (pmax top), and area under the curve (AUC). HFPO-DA and HFPO-DA-AS were the most potent (lowest EC 20, highest pmax top and AUC) of all PFAS in rat and human PPARα assays, being slightly less potent than oleic and linoleic acid, while NBP2 was the most potent in rat and human PPARγ assays. Only PFHxS, 8:2 and 6:2 FTOH exhibited hER agonism >20% pmax. In vitro measures of human and rat PPARα and PPARγ activity did not correlate with oral doses or serum concentrations of PFAS that induced increases in male rat liver weight from the National Toxicology Program 28-d toxicity studies. Data indicate that both PPARα and PPARγ activation may be molecular initiating events that contribute to the in vivo effects observed for many PFAS.
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“Interestingly, in vitro measurements of PPARα and PPARγ activity in human and rat models did not correlate with the oral doses or serum concentrations of PFAS that were associated with increased liver weights in male rats, as observed in National Toxicology Program 28-day toxicity studies [52].”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [52]
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Insight into the binding model of per- and polyfluoroalkyl substances to proteins and membranes
Zhao, L., Teng, M., Zhao, X., Li, Y., Sun, J., Zhao, W., Ruan, Y., Leung, K., & Wu, F. (2023) · Environment International · doi:10.1016/j.envint.2023.107951 · Cited by 236
Gaillard, L., Barouki, R., Blanc, É., Coumoul, X., & Andréau, K. (2024) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2024.07.021 · Cited by 140
The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science
Spyrakis, F., & Dragani, T. A. (2023) · Toxics · doi:10.3390/toxics11090721 · Cited by 78
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Effects of PFAS on human liver transporters: implications for health outcomes
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Metadata
- Authors
- Evans, N., Conley, J. M., Cardon, M., Hartig, P., Medlock-Kakaley, E., & Gray, L. E.
- Affiliations
- Environmental Protection Agency (US)
- Corresponding author
- Conley, Justin M.
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 449
- Pages
- 116136
- ISSN
- 0041-008X (ISSN-L)
- PMC
- PMC9341220
- OpenAlex
- W4283375803
- Cited by
- 208
- References
- 72
- Citations by year
- 2026: 53 · 2025: 73 · 2024: 51 · 2023: 29 · 2022: 2
- FWCI
- 13.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- per- and polyfluoroalkyl substances, PPARα, PPARγ, estrogen receptor, nuclear receptor activation, HFPO-DA, fatty acids, clofibric acid, clofibrate, Wy-14,643, PFOS, PFHxS, molecular initiating events, liver weight, endocrine disruptors
- MeSH terms
- Animals, Fatty Acids, Female, Fluorocarbons, Ligands, Male, Receptors, Estrogen, PPAR alpha, PPAR gamma, Rats
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