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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
Citation:
Evans, N., J. Conley, M. Cardon, P. Hartig, E. Medlock Kakaley, AND L. Gray. 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. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, 449:116136, (2022). https://doi.org/10.1016/j.taap.2022.116136
Impact/Purpose:
Per- and poly-fluoroalkyl substance (PFAS) research is of critical importance to USEPA and other health and regulatory organizations across the US and globally due to the nearly ubiquitous human and environmental exposure to multiple compounds in this chemical class. There is a need to more thoroughly evaluate the molecular initiating events across the PFAS chemical space in a variety of mechanistic in vitro capacities not limited to high-throughput approaches. Multiple PFAS have been demonstrated to activate peroxisome proliferator activated receptor alpha (PPARα), but less work has been done to investigate PFAS activation of PPAR beta (PPARβ) or gamma (PPARγ), or the steroid hormone nuclear receptors (estrogen (ER), androgen (AR), and glucocorticoid (GR)). Here, we investigated the in vitro receptor activity of a panel of 16 PFAS, 3 endogenous fatty acids, and 3 pharmaceuticals for PPARα, PPARβ, PPARγ, ER, AR, and GR activity. The data from this project will be useful to state, federal, and international regulatory agencies in the development of hazard and risk assessments on PFAS. This study clearly demonstrates that many PFAS activate both PPARα and PPARγ and a subset of PFAS also activate ER. This is important for characterizing PFAS-relevant Adverse Outcome Pathways as PPARα and PPARγ activation are critical molecular initiating events. The data presented here will be highly valuable for regulators and risk assessors to make scientifically based decisions on the potential adverse effects of PFAS and PFAS mixtures. We identified that HFPO-DA (GenX) was the most potent activator of both PPARα and PPARγ out of the panel of 16 PFAS investigated and was similar to endogenous PPAR ligands oleic and linoleic acid. Importantly, no metric of in vitro receptor activation was correlated with oral doses producing increases in rodent liver weights from in vivo toxicity studies of similar PFAS. A few PFAS did activated ER and follow-up studies should investigate the in vivo ER activity of these PFAS from oral exposures.
Description:
This sub-product will describe data generated from in vitro receptor binding assays for peroxisome proliferator activated receptor alpha, beta/delta, and gamma for a range of PFAS, fatty acids, and clofibric acid. Addtionally, these compounds were tested for in vitro estrogen, androgen, and glucocorticoid receptor transcriptional activaition. The manuscript will report measures of chemical efficacy and potency in each of the assays and will provide molecular initiating event information for AOP development.
