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

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.

In rats, GenX at 0.1−100nM0.1-100nM<math><mrow><mn>0.1</mn><mo>-</mo><mn>100</mn><mtext> </mtext><mtext>nM</mtext></mrow></math> rapidly (in 1-2 h) inhibited P-gp and BCRP transport activities at the BBB through different mechanisms. PPARγPPARγ<math><mrow><mtext>PPAR</mtext><mi>γ</mi></mrow></math> was required for the GenX effects on P-gp but not BCRP transport activity. https://doi.org/10.1289/EHP5884.

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 in vitro. Western blotting determined P-gp and BCRP protein levels. Cell survival after GenX exposure was determined for two human cell lines.

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 in vitro transport assay system. Reductions of P-gp but not BCRP transport activity were blocked by a peroxisome proliferator-activated receptor γγ<math><mi>γ</mi></math> (PPARγPPARγ<math><mrow><mtext>PPAR</mtext><mi>γ</mi></mrow></math>) antagonist. GenX reduced P-gp and BCRP transport activity in human cells.