title: Correlation between Conjugated Bisphenol A Concentrations and Efflux Transporter Expression in Human Fetal Livers.
abstract: Because of its widespread use in the manufacturing of consumer products over several decades, human exposure to bisphenol A (BPA) has been pervasive. Fetuses are particularly sensitive to BPA exposure, with a number of negative developmental and reproductive outcomes observed in rodent perinatal models. Xenobiotic transporters are one mechanism to extrude conjugated and unconjugated BPA from the liver. In this study, the mRNA expression of xenobiotic transporters and relationships with total, conjugated, and free BPA levels were explored utilizing human fetal liver samples. The mRNA expression of breast cancer resistance protein (BCRP) and multidrug resistance-associated transporter (MRP)4, as well as BCRP and multidrug resistance transporter 1 exhibited the highest degree of correlation, with r(2) values of 0.941 and 0.816 (P < 0.001 for both), respectively. Increasing concentrations of conjugated BPA significantly correlated with high expression of MRP1 (P < 0.001), MRP2 (P < 0.05), and MRP3 (P < 0.05) transporters, in addition to the NF-E2-related factor 2 transcription factor (P < 0.001) and its prototypical target gene, NAD(P)H quinone oxidoreductase 1 (P < 0.001). These data demonstrate that xenobiotic transporters may be coordinately expressed in the human fetal liver. This is also the first report of a relationship between environmentally relevant fetal BPA levels and differences in the expression of transporters that can excrete the parent compound and its metabolites.
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (J.E.M., L.M.A.); Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan (M.S.N., D.C.D.); Division of Environmental Health, School of Public Health, Georgia State University, Atlanta, Georgia (S.L.S.); Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey (S.L.S.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (S.L.S., L.M.A.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.L.S.); and Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan (D.C.D.).
authors: Jamie E
authors: JE
authors: Moscovitz
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (J.E.M., L.M.A.); Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan (M.S.N., D.C.D.); Division of Environmental Health, School of Public Health, Georgia State University, Atlanta, Georgia (S.L.S.); Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey (S.L.S.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (S.L.S., L.M.A.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.L.S.); and Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan (D.C.D.).
authors: Muna S
authors: MS
authors: Nahar
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (J.E.M., L.M.A.); Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan (M.S.N., D.C.D.); Division of Environmental Health, School of Public Health, Georgia State University, Atlanta, Georgia (S.L.S.); Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey (S.L.S.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (S.L.S., L.M.A.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.L.S.); and Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan (D.C.D.).
authors: Stuart L
authors: SL
authors: Shalat
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (J.E.M., L.M.A.); Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan (M.S.N., D.C.D.); Division of Environmental Health, School of Public Health, Georgia State University, Atlanta, Georgia (S.L.S.); Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey (S.L.S.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (S.L.S., L.M.A.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.L.S.); and Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan (D.C.D.).
authors: Angela L
authors: AL
authors: Slitt
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (J.E.M., L.M.A.); Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan (M.S.N., D.C.D.); Division of Environmental Health, School of Public Health, Georgia State University, Atlanta, Georgia (S.L.S.); Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey (S.L.S.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (S.L.S., L.M.A.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.L.S.); and Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan (D.C.D.).
authors: Dana C
authors: DC
authors: Dolinoy
authors: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey (J.E.M., L.M.A.); Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan (M.S.N., D.C.D.); Division of Environmental Health, School of Public Health, Georgia State University, Atlanta, Georgia (S.L.S.); Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey (S.L.S.); Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey (S.L.S., L.M.A.); Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.L.S.); and Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan (D.C.D.) aleksunes@eohsi.rutgers.edu.
authors: Lauren M
authors: LM
authors: Aleksunes
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000378:metabolism*; D001692:Biological Transport; D004785:Environmental Pollutants / Q000378:metabolism*; D005260:Female; D005865:Gestational Age; D065669:Hepatobiliary Elimination; D006801:Humans; D008099:Liver / Q000196:embryology / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001559:Benzhydryl Compounds; D004785:Environmental Pollutants; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D050984:NF-E2 Transcription Factor, p45 Subunit; D009363:Neoplasm Proteins; D010636:Phenols; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C116614:ABCG2 protein, human; C494692:NFE2 protein, human; C114462:multidrug resistance-associated protein 3; C447479:NQO1 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C421109:multidrug resistance-associated protein 1