Functional and Transcriptional Disruption of Hepatic ABC Transporters by Environmentally Relevant Short-Chain Per- and Polyfluoroalkyl Substances (PFAS).

Per- and polyfluoroalkyl substances (PFAS) represent a large class of > 11,000 synthetic organofluorine compounds that are globally distributed and consistently detected in human serum. Recent studies suggest that environmentally relevant exposures to short-chain PFAS can disrupt ATP-binding cassette (ABC) transporters, which regulate xenobiotic disposition and are critical for human health. This study examined the effects of short-term (45 min) and long-term (48 h) exposures to 1 nM or 1 µM of four short-chain PFAS, perfluorobutanesulfonic acid (PFBS), perfluorohexanoic acid (PFHxA), perfluorohexanesulfonic acid (PFHxS), and 6:2 fluorotelomer alcohol (6:2 FTOH), using differentiated HepaRG hepatocytes. Functional assays evaluated changes in efflux activity, while gene expression analysis quantified transcriptional responses across 38 ABC transporters. Following 48-h exposures, both 1 nM and 1 µM treatments significantly decreased the retention of fluorescent substrates CMFDA, BODIPY-cholesterol, Hoechst 33342, and Rhodamine 123 relative to controls, indicating enhanced efflux transporter activity. Consistent with these results, transcriptional analysis revealed significant upregulation of multiple ABC genes, including ABCG2 (BCRP), ABCB1 (P-gp/MDR1), and ABCC1 (MRP1). In contrast, short-term exposures produced no measurable effects on efflux activity. Together, these findings demonstrate that environmentally relevant concentrations of short-chain PFAS can alter the expression and activity of key hepatic ABC transporters. Such changes may disrupt the handling of endogenous compounds and pharmaceuticals, raising concerns that low-level PFAS exposure could influence drug disposition and human health outcomes.