Cited by 208Per- and polyfluoroalkyl substances researchPeroxisome Proliferator-Activated ReceptorsEffects and risks of endocrine disrupting chemicals

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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

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Evans, Nicola, Conley, Justin M., Cardon, Mary, Hartig, Phillip, Medlock-Kakaley, Elizabeth, Gray, L. Earl·2022·Toxicology and Applied Pharmacology

DOI 10.1016/j.taap.2022.116136PMC PMC9341220

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Abstract

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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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.
ORCID: Evans, Nicola
Conley, Justin M.
Medlock-Kakaley, Elizabeth
Gray, L. Earl
Venue: Toxicology and Applied Pharmacology
Publisher: Elsevier BV
Published: 2022-08
Volume: 449
Pages: 116136
ISSN: 0041-008X (ISSN-L)
DOI: 10.1016/j.taap.2022.116136
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
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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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

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