四溴双酚 A（TBBPA）改变血脑屏障的 ABC 转运体。
Tetrabromobisphenol A (TBBPA) Alters ABC Transport at the Blood-Brain Barrier.
机构信息
Laboratory of Toxicology and Toxicokinetics, National Cancer Institute, National Institutes of Health, Research Triangle Park, North Carolina 27709.
University of North Carolina School of Medicine, Chapel Hill, North Carolina 27516.
出版信息
Toxicol Sci. 2019 Jun 1;169(2):475-484. doi: 10.1093/toxsci/kfz059.
Tetrabromobisphenol A (TBBPA, CAS No. 79-94-7) is a brominated flame retardant used in 90% of epoxy coated circuit boards. Exposures to TBBPA can induce neurotoxicity and disrupt MAPK, estrogen, thyroid, and PPAR-associated signaling pathways. Because these pathways also regulate transporters of the central nervous system barriers, we sought to determine the effect of TBBPA on the expression and activity of 3 ATP binding cassette (ABC) transporters of the blood-brain barrier (BBB). Using a confocal based assay, we measured the ex vivo and in vivo effects of TBBPA on P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) transport activity in rat brain capillaries. Our rationale for using a rat model was based on tissue availability, ease of handling, and availability of historical TBBPA toxicokinetic data. We found that TBBPA (1-1000 nM) exposure had no significant effect on multidrug resistance-associated protein 2 transport activity in either sex, suggesting TBBPA does not compromise the physical integrity of the BBB. However, low concentrations of TBBPA (1-100 nM) significantly decreased breast cancer resistant protein transport activity in both sexes. Additionally, TBBPA exposures (1-100 nM), elicited a sex-dependent response in P-gp transport: increasing transport activity in males and decreasing transport activity in females. All TBBPA dependent changes in transport activity were dose- and time-dependent. Inhibitors of either transcription or translation abolished the TBBPA dependent increases in male P-gp transport activity. Western blot and immunofluorescent assays confirmed the TBBPA dependent P-gp increases expression in males and decreases in females. Antagonizing PPAR-γ abolished the TBBPA dependent increases in males but not the decreases in females. However, the decreases in female P-gp transport were blocked by an ER-α antagonist. This work indicates that environmentally relevant concentrations of TBBPA (1-100 nM) alter ABC transporter function at the BBB. Moreover, permeability changes in the BBB can alter brain homeostasis, hinder central nervous system drug delivery, and increase the brain's exposure to harmful xenobiotic toxicants.
四溴双酚 A（TBBPA，CAS 号 79-94-7）是一种溴化阻燃剂，用于 90%的环氧涂层电路板。接触 TBBPA 会引起神经毒性，并破坏 MAPK、雌激素、甲状腺和 PPAR 相关信号通路。由于这些通路也调节中枢神经系统屏障的转运体，我们试图确定 TBBPA 对血脑屏障（BBB）中 3 种 ATP 结合盒（ABC）转运体的表达和活性的影响。我们使用基于共聚焦的测定法，测量了 TBBPA 在体外和体内对大鼠脑毛细血管中 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）转运活性的影响。我们选择使用大鼠模型的理由是基于组织可用性、处理的便利性以及 TBBPA 毒代动力学数据的可用性。我们发现，TBBPA（1-1000 nM）暴露对两性的多药耐药相关蛋白 2 转运活性均无显著影响，这表明 TBBPA 不会损害 BBB 的物理完整性。然而，低浓度的 TBBPA（1-100 nM）显著降低了两性的乳腺癌耐药蛋白转运活性。此外，TBBPA 暴露（1-100 nM）在雄性中引发了 P-gp 转运的性别依赖性反应：增加了转运活性，而在雌性中则降低了转运活性。所有 TBBPA 依赖性转运活性变化均呈剂量和时间依赖性。转录或翻译抑制剂消除了 TBBPA 依赖性雄性 P-gp 转运活性的增加。Western blot 和免疫荧光测定证实，TBBPA 依赖性雄性 P-gp 表达增加，而雌性表达减少。拮抗 PPAR-γ 消除了 TBBPA 依赖性雄性的增加，但对雌性没有影响。然而，雌性 P-gp 转运的减少被 ER-α 拮抗剂阻断。这项工作表明，环境相关浓度的 TBBPA（1-100 nM）会改变 BBB 中的 ABC 转运体功能。此外，BBB 的通透性变化会改变脑内稳态，阻碍中枢神经系统药物输送，并增加大脑对有害外源性毒物的暴露。
Zotero 插件