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

Environ Health Perspect. 2020 Mar;128(3):37002. doi: 10.1289/EHP5884. Epub 2020 Mar 26.

Abstract

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 in vitro. 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 in vitro transport assay system. Reductions of P-gp but not BCRP transport activity were blocked by a peroxisome proliferator-activated receptor γ (PPARγ) antagonist. GenX reduced P-gp and BCRP transport activity in human cells.

Conclusion: In rats, GenX at 0.1-100 nM rapidly (in 1-2 h) inhibited P-gp and BCRP transport activities at the BBB through different mechanisms. PPARγ was required for the GenX effects on P-gp but not BCRP transport activity. https://doi.org/10.1289/EHP5884.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Female
  • Fluorocarbons / adverse effects*
  • Male
  • Propionates / adverse effects*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Abcg2 protein, rat
  • Fluorocarbons
  • Propionates
  • ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate