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ToxSci Advance Access originally published online on June 12, 2007
Toxicological Sciences 2007 99(1):118-125; doi:10.1093/toxsci/kfm148
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Metabolic Barrier against Bisphenol A in Rat Uterine Endometrium

Junya Matsumoto*, Hidetomo Iwano*, Hiroki Inoue{dagger}, Naomi Iwano*, Naoko Yamashiki{ddagger} and Hiroshi Yokota*,1

* Department of Veterinary Biochemistry, School of Veterinary Medicine {dagger} Department of Environmental Biochemistry {ddagger} Department of Biology, Faculty of Environmental System, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan 069-8501

1 To whom correspondence should be addressed at Laboratory of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan. Fax: +81-11-387-5890. E-mail: h-yokota{at}rakuno.ac.jp.

Received March 9, 2007; accepted June 1, 2007


  Abstract

Exposure to environmental chemicals with estrogenic activity during the early stage of pregnancy can seriously affect embryonic development and the maintenance of pregnancy. To estimate the metabolism and pharmacodynamics of a xenoestrogen, bisphenol A, in a reproductive organ, the metabolite of bisphenol A was analyzed after incubating a rat uterine sac in buffer solutions containing the chemical. When the inner or the outer side of the uterine sac was exposed to bisphenol A, the concentration of the parent chemical was decreased in buffer solution and then, only one metabolite, bisphenol A-glucuronide, was observed only in the outer, that is, the maternal, side. A small amount of the parent chemical could pass through the uterine sac without being modified. Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) was shown by immunohistochemical staining analysis to be distributed in epithelial cells of the endometrium, oviduct, and uterine glands. Based on measurements of enzyme activity and on Western blot analysis, UGT activity toward bisphenol A and UGT protein were identified in the microsomal fractions prepared from rat uterus. UGT isoforms, such as UGT1A1, 1A2, 1A5, 1A6, and 1A7, were expressed, and MRP-1 (multidrug resistance-associated protein) and MRP-3, which are well-known to be transporters of various drug-glucuronides, were detected in the rat uterus by reverse transcription-PCR. These results elucidate the rat uterine barrier system by showing that most bisphenol A perfused into the uterus was glucuronidated in the epithelium, resulting in transport of glucuronides to the maternal side.

Key Words: bisphenol A; uterus; UDP-glucuronosyltransferase; drug-barrier; endometrial cells.


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