Placental Transfer of Conjugated Bisphenol A and Subsequent Reactivation in the Rat Fetus

• Published in: Environmental health perspectives Vol. 118; no. 9; pp. 1196 - 1203
• Main Authors: Nishikawa, Miyu, Iwano, Hidetomo, Yanagisawa, Risa, Koike, Nanako, Inoue, Hiroki, Yokota, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences 01.09.2010
• Subjects: Activation; Amniotic fluid; Amniotic Fluid - metabolism; Animals; Benzhydryl Compounds; Bisphenol A; Bisphenols; Blood; Chromatography, High Pressure Liquid; Drug metabolism; Drugs; Endocrine disruptors; Environmental health; Female; Fetus; Fetus - metabolism; Glucuronides; Glucuronides - metabolism; Health aspects; Immunohistochemistry; Liver; Mass Spectrometry; Membranes; Metabolites; Perfusion; Phenols - metabolism; Placenta; Placenta - metabolism; Polypeptides; Position (location); Pregnancy; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Trophoblasts; Japan
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.0901575

Background: Bisphenol A (BPA), a well-known endocrine disruptor, is highly glucuronidated in the liver, and the resultant BPA-glucuronide (BPA-GA) is excreted primarily into bile. However, in rodents, prenatal exposure to low doses of BPA can adversely affect the fetus, despite the efficient drug-metabolizing systems of the dams. The transport mechanisms of BPA from mother to fetus are unknown. Objectives: To test our hypothesis that BPA-GA—an inactive metabolite—is passed through the placenta to the fetus, where it affects the fetus after reactivation, we investigated the placental transfer of BPA-GA and reactivation to BPA in the fetus. Methods: After performing uterine perfusion with BPA-GA in pregnant rats, we examined the expression and localization of the placental transporters for drug metabolites in the perfusate by reverse-transcriptase polymerase chain reaction and immunohistochemistry. We also investigated the deconjugation of BPA-GA in the fetus and examined uridine 5′-diphospho-glucuronosyltransferase (UGT) activity toward BPA and the expression of UGT isoforms in fetal liver. Results: We detected BPA-GA and deconjugated BPA in the fetus and amniotic fluid after perfusion. In the trophoblast cells, organic anion-transporting polypeptide 4a1 (Oatp4a1) was localized on the apical membrane, and multidrug resistance-associated protein 1 (Mrp1) was localized to the basolateral membrane. We observed deconjugation of BPA-GA in the fetus; furthermore, we found the expression of UGT2B1, which metabolizes BPA, to be quite low in the fetus. Conclusions: These results demonstrate that BPA-GA is transferred into the fetus and deconjugated in the fetus because of its vulnerable drug-metabolizing system.