Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Obstetrics and Gynecology, Maternal-fetal Pharmacology and Biodevelopment Laboratories, The University of Texas Medical Branch, Galveston, TX 77555, USA.
Department of Obstetrics and Gynecology, Maternal-fetal Pharmacology and Biodevelopment Laboratories, The University of Texas Medical Branch, Galveston, TX 77555, USA.
Toxicol Appl Pharmacol. 2018 Nov 15;359:47-54. doi: 10.1016/j.taap.2018.09.022. Epub 2018 Sep 19.
Exposure to bisphenols (BPA and BPS) during pregnancy can significantly affect fetal development and increase risk of adverse health consequences, however the underlying mechanisms are not fully elucidated. In human placenta, the efflux transporter P-glycoprotein (P-gp), encoded by the ABCB1 gene, extrudes its substrates from the trophoblasts back into the maternal circulation. Alterations in levels of placental P-gp could therefore significantly affect fetal exposure to xenobiotics that are P-gp substrates. The ABCB1 promoter contains many single nucleotide polymorphisms (SNPs). In the genome, SNPs are not arrayed as independent variants but as combinations forming defined haplotypes. Recently, we determined the haplotype sequences encompassing the ABCB1 promoter SNPs and found that promoter haplotypes differentially affect ABCB1 promoter activity. Here we investigate the effect of BPA and BPS on ABCB1 promoter activity by testing the hypothesis that BPA and BPS exposure affect ABCB1 promoter activity in a haplotype-dependent manner. Our data indicate that acute exposure to 50 nM BPA induced a significant haplotype-dependent increase in ABCB1 promoter activity (P < .05). However, acute exposure to 0.5 nM BPS induced a significant decrease (P < .05) in promoter activity that was haplotype-dependent. Chronic exposure to BPA and BPS individually (5 nM and 0.3 nM, respectively) or as a mixture (5 nM BPA:1.5 nM BPS) induced significant haplotype-dependent increases (P < .01) in ABCB1 promoter activity. Our data indicate that BPA and BPS significantly alter ABCB1 promoter activity in a haplotype- and exposure type- dependent manners. Such alteration could significantly impact placental P-gp levels and alter fetal exposure to many therapeutic and environmental xenobiotics.
怀孕期间接触双酚（BPA 和 BPS）会显著影响胎儿发育并增加不良健康后果的风险，但潜在机制尚未完全阐明。在人胎盘组织中，外排转运蛋白 P-糖蛋白（P-gp）由 ABCB1 基因编码，将其底物从滋养层中挤出回到母体循环中。因此，胎盘 P-gp 水平的改变可能会显著影响胎儿暴露于 P-gp 底物的外源性化学物质。ABCB1 启动子包含许多单核苷酸多态性（SNP）。在基因组中，SNP 不是作为独立的变体排列，而是作为形成定义单倍型的组合排列。最近，我们确定了包含 ABCB1 启动子 SNP 的单倍型序列，并发现启动子单倍型差异影响 ABCB1 启动子活性。在这里，我们通过测试 BPA 和 BPS 暴露以单倍型依赖的方式影响 ABCB1 启动子活性的假设来研究 BPA 和 BPS 对 ABCB1 启动子活性的影响。我们的数据表明，急性暴露于 50 nM BPA 以单倍型依赖的方式显著诱导 ABCB1 启动子活性增加（P <.05）。然而，急性暴露于 0.5 nM BPS 诱导启动子活性显著降低（P <.05），这也是单倍型依赖的。慢性暴露于 BPA 和 BPS 单独（分别为 5 nM 和 0.3 nM）或作为混合物（5 nM BPA：1.5 nM BPS）以单倍型依赖的方式诱导 ABCB1 启动子活性显著增加（P <.01）。我们的数据表明，BPA 和 BPS 以单倍型和暴露类型依赖的方式显著改变 ABCB1 启动子活性。这种改变可能会显著影响胎盘 P-gp 水平，并改变胎儿对许多治疗性和环境外源性化学物质的暴露。
