Bisphenol A (BPA) and bisphenol S (BPS) alter the promoter activity of the ABCB1 gene encoding P-glycoprotein in the human placenta in a haplotype-dependent manner

Abstract

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.

Fetal–Maternal Exposure to Endocrine Disruptors: Correlation with Diet Intake and Pregnancy Outcomes

“…The BPA-substitute BPS was reported to alter the placental expression of the efflux transporter P-glycoprotein (P-gp), one of the main regulators of fetal exposure to xenobiotics encoded by the ABCB1 gene. Using CRL-1584 human trophoblast cell lines, Speidel and colleagues demonstrated that acute exposure to BPS (0.5 nM) induced a significant haplotype-dependent decrease in ABCB1 promoter activity, while chronic BPS exposure (0.3 nM) induced a significant haplotype-dependent promoter activity increase, thus dramatically impacting on P-gp levels and fetal exposure to xenobiotics coming from the maternal circulation [ 92 ]. Moreover, prenatal exposure to BPS (5 mg/kg/d) in C57BL/6 N mice was described to increase the susceptibility to high-fat-diet-induced adipogenesis in F1 male adult mice via the upregulation of PPAR-γ and its target genes [ 93 ].…”

Bisphenol A and bisphenol S disruptions of the mouse placenta and potential effects on the placenta–brain axis

“…studies have focused on the effects of BPA in isolated human placenta lines and in term human placenta (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). A concern with using cells derived from human term tissues is that they fail to replicate the full range of placental responses associated with the critical early and midpregnancy periods (34).…”

Early Life Exposure to Food Contaminants and Social Stress as Risk Factor for Metabolic Disorders Occurrence?—An Overview

“…Speidel and colleagues demonstrated that acute exposure to BPS (0.5 nM) induced a significant haplotype-dependent decrease in ABCB1 promoter activity in CRL-1584 human trophoblast cell lines. However, chronic BPS exposure (0.3 nM) induced a significant haplotype-dependent promoter activity increase, impacting P-gp levels and fetal exposure to xenobiotics coming from the maternal circulation [ 158 ].…”