Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 449, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2022.116136
Keywords
Mechanism of action; Molecular initiating event; GenX; Bioactivity; Adverse outcome pathway
Categories
Funding
- U.S. Environmental Protection Agency Chemical Safety for Sustainability Research Action Plan
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Data demonstrate that numerous PFAS activate PPAR alpha and PPAR gamma, while some compounds like FTOH and PFOSA do not. HFPO-DA and HFPO-DA-AS were the most potent in PPAR alpha assays, while NBP2 showed the highest potency in PPAR gamma assays.
Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPAR alpha), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPAR gamma) and other nuclear receptors. We utilized in vitro assays with either human or rat PPAR alpha or PPAR gamma 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 PPAR alpha and PPAR gamma 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% (EC20), 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 EC20, highest pmax(top) and AUC) of all PFAS in rat and human PPAR alpha assays, being slightly less potent than oleic and linoleic acid, while NBP2 was the most potent in rat and human PPAR gamma assays. Only PFHxS, 8:2 and 6:2 FTOH exhibited hER agonism > 20% pmax. In vitro measures of human and rat PPAR alpha and PPAR gamma 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 PPAR alpha and PPAR gamma activation may be molecular initiating events that contribute to the in vivo effects observed for many PFAS.
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