Placental transfer of conjugated bisphenol A and subsequent reactivation in the rat fetus.
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.


OBJECTIVE
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.
Nishikawa
Miyu
M
Laboratory of Veterinary Biochemistry, Department of Bioscience, School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan.
Iwano
Hidetomo
H
Yanagisawa
Risa
R
Koike
Nanako
N
Inoue
Hiroki
H
Yokota
Hiroshi
H
D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005333:Fetus / Q000378:metabolism*; D020719:Glucuronides / Q000378:metabolism*; D007150:Immunohistochemistry; D013058:Mass Spectrometry; D010636:Phenols / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D020719:Glucuronides; D010636:Phenols; C512161:bisphenol A glucuronide; D000098826:Bisphenol A Compounds
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