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标题：Effect of GenX on P-Glycoprotein, Breast Cancer Resistance Protein, and Multidrug Resistance–Associated Protein 2 at the Blood–Brain Barrier
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作者：Ronald E. Cannon ; Alicia C. Richards ; Andrew W. Trexler 等
期刊名称：Environmental Health Perspectives
印刷版ISSN：0091-6765
电子版ISSN：1552-9924
出版年度：2020
卷号：128
期号：3
页码：1-10
DOI：10.1289/EHP5884
出版社：OCR Subscription Services Inc
摘要：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 ( PPAR γ ) 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. PPAR γ was required for the GenX effects on P-gp but not BCRP transport activity.