Effects of exposure in utero to bisphenol a on the expression of aryl hydrocarbon receptor, related factors, and xenobiotic metabolizing enzymes in murine embryos.
To evaluate the effects of bisphenol A (BPA), a candidate endocrine disruptor (ED), on embryonic development, we examined the mRNA expression levels of the aryl hydrocarbon receptor (AhR; which binds with many EDs and plays crucial roles in their metabolism) and related factors [aryl hydrocarbon receptor repressor (AhRR) and AhR nuclear translocator (Arnt)], xenobiotic metabolizing enzymes [XMEs; cytochrome P450 1A1 (CYP1A1) and UDP-glucuronosyltransferase, and the glutathione S-transferase Ya subunit (GST)], in murine embryos exposed in utero to BPA (0.02, 2, 200, and 20,000 microg/kg/day) and 17beta-estradiol (E2; 5 microg/kg/day, used as a positive control) at 6.5-13.5 or 6.5-17.5 days post coitum (dpc) using the quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) method. Protein levels of CYP1A1 and GST in embryonic livers were estimated by Western immunoblotting. Exposure in utero to BPA [0.02 (1/100 dose of environmental exposure), 2, 200, and 20,000 microg/kg/day] increased AhR mRNA expression in the cerebra, cerebella, and gonads (testes and ovaries) of male and female mid-and late-developmental stage (14.5- and 18.5-dpc, respectively) embryos. BPA dose-independently up-regulated the expression of AhRR and Arnt in mid- and late-stage embryos. BPA had no remarkable effect on the mRNA levels of XMEs in mid-stage embryos, but dose-dependently up-regulated the expression in late-stage embryos. Moreover, the protein levels of these enzymes in the livers of late-stage embryos were increased. The present findings revealed that exposure to BPA in utero disrupts the expression of AhR and related factors and of xenobiotic metabolizing enzymes, and that mid-stage embryos, in the organogenic stage, are sensitive to BPA.
Nishizawa
Hanako
H
Research Unit for Animal Life Sciences, Animal Resource Science Center, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Ibaraki-Iwama, Japan.
Imanishi
Satoshi
S
Manabe
Noboru
N
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D001559:Benzhydryl Compounds; D015153:Blotting, Western; D002531:Cerebellum / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects*; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006066:Gonads / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D010636:Phenols / Q000378:metabolism* / Q000633:toxicity; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013687:Telencephalon / Q000378:metabolism; D000098826:Bisphenol A Compounds
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D001559:Benzhydryl Compounds; D019363:Cytochrome P-450 CYP1A1; D004968:Estrogens, Non-Steroidal; D005982:Glutathione Transferase; D010636:Phenols; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C117300:Ahrr protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds