Liver and Intestinal Fatty Acid Binding Proteins Are Not Critical for Perfluorooctanesulfonate (PFOS) Tissue Distribution and Elimination in Mice

Abstract

Perfluorooctanesulfonate (PFOS) is a persistent environmental pollutant in the per- and polyfluoroalkyl substances (PFAS) class, known to accumulate in the liver and trigger hepatotoxicity. While in vitro studies suggested that fatty acid-binding proteins (FABPs) drive the hepatic accumulation of PFAS, in vivo evidence is entirely lacking. Using wild-type and mice with global deletion of liver-type and intestine-type FABP (L-FABP^–/–, I-FABP^–/–), we measured PFOS toxicokinetics by administering single oral doses (0.1, 0.5, and 5 mg/kg) and tracking blood and excreta levels for 65 days. PFOS levels in various tissues were measured at test end. Additionally, we measured PFAS binding to liver tissues from wild-type and FABP knockout mice. Contrary to previous in vitro findings, FABP deletion did not significantly alter PFOS blood concentrations, tissue distribution, or elimination rates. Elimination half-lives, clearances, and volumes of distribution were consistent across genotypes, suggesting that neither L-FABP nor I-FABP are critical drivers for PFOS in vivo toxicokinetics. In vitro binding assays showed similar liver partition coefficients between wild-type and knockout livers for 15 of 19 PFAS, with small differences for some sulfonamides and fluorotelomer sulfonates. These results challenge the presumed role of L-FABP and/or I-FABP in PFAS toxicokinetics, highlighting the need to explore alternative toxicokinetic mechanisms─such as phospholipid binding and transporter-mediated uptake─driving PFAS distribution and elimination.