Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance-Associated Protein 2 at the Blood-Brain Barrier.

Background: Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid (GenX) is a replacement for perfluorooctanoic acid in the production of fluoropolymers used in a variety of consumer products. GenX alters fetal development and antibody production and elicits toxic responses in the livers and kidneys of rodents. The GenX effect on the blood-brain barrier (BBB) is unknown. The BBB protects the brain from xenobiotic neurotoxicants and harmful endogenous metabolites.

Objectives: We aimed to investigate the effects of GenX on the transport activity and expression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) at the BBB.

Methods: Transporter activities were measured in isolated rat brain capillaries by a confocal microscopy-based method. ATPase (enzymatic hydrolysis of adenosine triphosphate to inorganic phosphate) levels were measured . Western blotting determined P-gp and BCRP protein levels. Cell survival after GenX exposure was determined for two human cell lines.

Results: Nanomolar levels of GenX inhibited P-gp and BCRP but not MRP2 transport activities in male and female rat brain capillaries. P-gp transport activity returned to control levels after GenX removal. GenX did not reduce P-gp- or BCRP-associated ATPase activity in an transport assay system. Reductions of P-gp but not BCRP transport activity were blocked by a peroxisome proliferator-activated receptor () antagonist. GenX reduced P-gp and BCRP transport activity in human cells.

Conclusion: In rats, GenX at rapidly (in 1-2 h) inhibited P-gp and BCRP transport activities at the BBB through different mechanisms. was required for the GenX effects on P-gp but not BCRP transport activity. https://doi.org/10.1289/EHP5884.