GenX 对血脑屏障上 P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白 2 的影响。

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

机构信息

Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

出版信息

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

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.

背景

2,3,3,3-四氟-2-(七氟丙氧基)丙酸铵（GenX）是用于各种消费品的氟聚合物生产中替代全氟辛酸的物质。GenX 会改变胎儿发育和抗体产生，并引起啮齿动物的肝脏和肾脏的毒性反应。GenX 对血脑屏障（BBB）的影响尚不清楚。BBB 可保护大脑免受外源性神经毒物和有害内源性代谢物的侵害。

目的

我们旨在研究 GenX 对 BBB 上 P-糖蛋白（P-gp）、乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白 2（MRP2）的转运活性和表达的影响。

方法

通过基于共聚焦显微镜的方法测量分离的大鼠脑毛细血管中的转运体活性。测量三磷酸腺苷酶（水解三磷酸腺苷生成无机磷酸）水平。Western blot 确定 P-gp 和 BCRP 蛋白水平。测定 GenX 暴露后两种人细胞系的细胞存活率。

结果

纳摩尔水平的 GenX 抑制雄性和雌性大鼠脑毛细血管中的 P-gp 和 BCRP 但不抑制 MRP2 转运活性。GenX 去除后 P-gp 转运活性恢复至对照水平。GenX 在转运测定系统中不会降低 P-gp 或 BCRP 相关的三磷酸腺苷酶活性。过氧化物酶体增殖物激活受体 (PPAR) 拮抗剂可阻断 P-gp 但不阻断 BCRP 转运活性的降低。GenX 降低了人细胞中的 P-gp 和 BCRP 转运活性。