Transport of Perfluoroalkyl Substances (PFAS) by Three Renal Transporters: Implications for PFAS Bioaccumulation Mechanisms

Abstract

The long biological half-lives of per- and polyfluoroalkyl substances (PFAS) in humans have been linked to interactions with renal transport proteins and polypeptides. However, only a limited number of kidney transporters have been studied for their ability to transport specific PFAS. Moreover, few studies have investigated whether PFAS alternatives serve as substrates for these transporters. In this study, we focused on one renal influx transporter, organic anion transporter 1 (OAT1) and two efflux transporters (P-glycoprotein (P-g) and breast cancer resistance protein (BCRP)) involved in PFAS excretion. We evaluated two well-studied PFAS, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS), along with two current substitutes. Hexafluoropropylene oxide dimer acid (HFPO-DA), the major component of the PFOA alternative GenX, was not transported by any of the studied renal transporters. In contrast, hexafluoropropylene oxide trimer acid (HFPO-TA), a minor component of GenX, as well as PFOA itself, were taken up by all studied transporters. Both PFOS and its tested alternative (F53B), including both major and minor components, were substrates of all tested renal transporters, with PFOS and F53B showing relatively higher transport activity. BCRP- and P-gp-mediated transport of five PFAS underwent a saturable process with Michaelis constant (K_m) ranging from 1.29 to 7.92 μmol/L and 1.41 to 2.78 μmol/L, respectively. The highest V_max/K_m ratio was observed for PFOA transport by P-gp (279 pmol/mg protein/min/(μmol/L)). To the best of our knowledge, this is the first study reporting interactions between renal transporters and these legacy PFAS replacements. These findings enhance our understanding of PFAS bioaccumulation at the cellular and molecular levels, offering key parameters for PFAS toxicokinetic modeling.