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

Jordan T. Speidel, Meixiang Xu, Sherif Abdel-Rahman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)47-54
Number of pages8
JournalToxicology and Applied Pharmacology
Volume359
DOIs
StatePublished - Nov 15 2018

Fingerprint

Gene encoding
P-Glycoprotein
Haplotypes
Placenta
Genes
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Xenobiotics
Substrates
bis(4-hydroxyphenyl)sulfone
bisphenol A
Trophoblasts
Fetal Development
Health
Mothers
Genome
Pregnancy
Testing

Keywords

  • ABCB1
  • BPA/BPS
  • Haplotypes
  • P-Glycoprotein
  • Placenta
  • Polymorphisms

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

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title = "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.",
keywords = "ABCB1, BPA/BPS, Haplotypes, P-Glycoprotein, Placenta, Polymorphisms",
author = "Speidel, {Jordan T.} and Meixiang Xu and Sherif Abdel-Rahman",
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TY - JOUR

T1 - 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

AU - Speidel, Jordan T.

AU - Xu, Meixiang

AU - Abdel-Rahman, Sherif

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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.

AB - 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.

KW - ABCB1

KW - BPA/BPS

KW - Haplotypes

KW - P-Glycoprotein

KW - Placenta

KW - Polymorphisms

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VL - 359

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JO - Toxicology and Applied Pharmacology

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