Abstract
Xenoestrogens, such as bisphenol A and diethylstilbestrol, are glucuronidated by an isoform of UDP-glucuronosyltransferase named UGT2B1 in the livers of adult male rats. In this study, we found that nonylphenol and octylphenol are also conjugated with glucuronic acid by adult rat liver microsomes. Although UDP-glucuronosyltransferase activities toward these xenoestrogens were not detected in the fetal rat liver, a linear increase in enzymatic activities during neonatal development was observed. At 3 weeks after birth, the activities had reached the same level as that of adult rats. The protein and mRNA contents of UGT2B1 also were not detected in the fetal rat liver, but a developmental increase in newborn rat liver was detected by Western and Northern blotting analysis. Additionally, rat hepatic microsomal UDP-glucuronosyltransferase activities toward these xenoestrogens were reduced by about half during pregnancy of mother rats. The results suggest that the reproductive organs of fetal and early-stage neonatal rats, which are sensitive to sex hormones, face a high risk of exposure to free active xenoestrogens.
Full Text
The Full Text of this article is available as a PDF (572.7 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Burchell B., Nebert D. W., Nelson D. R., Bock K. W., Iyanagi T., Jansen P. L., Lancet D., Mulder G. J., Chowdhury J. R., Siest G. The UDP glucuronosyltransferase gene superfamily: suggested nomenclature based on evolutionary divergence. DNA Cell Biol. 1991 Sep;10(7):487–494. doi: 10.1089/dna.1991.10.487. [DOI] [PubMed] [Google Scholar]
- Gueraud F., Masmoudi T., Goudonnet H., Paris A. Differential effect of hypophysectomy and growth hormone treatment on hepatic glucuronosyltransferases in male rats: evidence for an action at a pretranslational level for isoforms glucuronidating bilirubin. Biochem Pharmacol. 1997 Jun 1;53(11):1637–1647. doi: 10.1016/s0006-2952(97)82452-5. [DOI] [PubMed] [Google Scholar]
- Howdeshell K. L., Hotchkiss A. K., Thayer K. A., Vandenbergh J. G., vom Saal F. S. Exposure to bisphenol A advances puberty. Nature. 1999 Oct 21;401(6755):763–764. doi: 10.1038/44517. [DOI] [PubMed] [Google Scholar]
- Howe J. G., Hershey J. W. A sensitive immunoblotting method for measuring protein synthesis initiation factor levels in lysates of Escherichia coli. J Biol Chem. 1981 Dec 25;256(24):12836–12839. [PubMed] [Google Scholar]
- Hull K. L., Harvey S. Growth hormone: roles in female reproduction. J Endocrinol. 2001 Jan;168(1):1–23. doi: 10.1677/joe.0.1680001. [DOI] [PubMed] [Google Scholar]
- Ikushiro S., Emi Y., Iyanagi T. Protein-protein interactions between UDP-glucuronosyltransferase isozymes in rat hepatic microsomes. Biochemistry. 1997 Jun 10;36(23):7154–7161. doi: 10.1021/bi9702344. [DOI] [PubMed] [Google Scholar]
- Imai Y. Reconstituted O-dealkylase systems containing various forms of liver microsomal cytochrome P-450. J Biochem. 1979 Dec;86(6):1697–1707. doi: 10.1093/oxfordjournals.jbchem.a132690. [DOI] [PubMed] [Google Scholar]
- Inoue H., Yokota H., Makino T., Yuasa A., Kato S. Bisphenol a glucuronide, a major metabolite in rat bile after liver perfusion. Drug Metab Dispos. 2001 Aug;29(8):1084–1087. [PubMed] [Google Scholar]
- Knaak J. B., Sullivan L. J. Metabolism of bisphenol A in the rat. Toxicol Appl Pharmacol. 1966 Mar;8(2):175–184. doi: 10.1016/s0041-008x(66)80001-7. [DOI] [PubMed] [Google Scholar]
- Kohri K., Nomura S., Kitamura Y., Nagata T., Yoshioka K., Iguchi M., Yamate T., Umekawa T., Suzuki Y., Sinohara H. Structure and expression of the mRNA encoding urinary stone protein (osteopontin). J Biol Chem. 1993 Jul 15;268(20):15180–15184. [PubMed] [Google Scholar]
- Krishnan A. V., Stathis P., Permuth S. F., Tokes L., Feldman D. Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology. 1993 Jun;132(6):2279–2286. doi: 10.1210/endo.132.6.8504731. [DOI] [PubMed] [Google Scholar]
- LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
- Li Y. Q., Prentice D. A., Howard M. L., Mashford M. L., Desmond P. V. The effect of hormones on the expression of five isoforms of UDP-glucuronosyltransferase in primary cultures of rat hepatocytes. Pharm Res. 1999 Feb;16(2):191–197. doi: 10.1023/a:1018812021549. [DOI] [PubMed] [Google Scholar]
- Sharpe R. M., Fisher J. S., Millar M. M., Jobling S., Sumpter J. P. Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production. Environ Health Perspect. 1995 Dec;103(12):1136–1143. doi: 10.1289/ehp.951031136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Soto A. M., Justicia H., Wray J. W., Sonnenschein C. p-Nonyl-phenol: an estrogenic xenobiotic released from "modified" polystyrene. Environ Health Perspect. 1991 May;92:167–173. doi: 10.1289/ehp.9192167. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watkins J. B., Klaassen C. D. Development of UDP-glucuronosyltransferase activity toward digitoxigenin-monodigitoxoside in neonatal rats. Drug Metab Dispos. 1985 Mar-Apr;13(2):186–191. [PubMed] [Google Scholar]
- White R., Jobling S., Hoare S. A., Sumpter J. P., Parker M. G. Environmentally persistent alkylphenolic compounds are estrogenic. Endocrinology. 1994 Jul;135(1):175–182. doi: 10.1210/endo.135.1.8013351. [DOI] [PubMed] [Google Scholar]
- Wishart G. J. Functional heterogeneity of UDP-glucuronosyltransferase as indicated by its differential development and inducibility by glucocorticoids. Demonstration of two groups within the enzyme's activity towards twelve substrates. Biochem J. 1978 Aug 15;174(2):485–489. doi: 10.1042/bj1740485. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yokota H., Ohgiya N., Ishihara G., Ohta K., Yuasa A. Purification and properties of UDP-glucuronyltransferase from kidney microsomes of beta-naphthoflavone-treated rat. J Biochem. 1989 Aug;106(2):248–252. doi: 10.1093/oxfordjournals.jbchem.a122839. [DOI] [PubMed] [Google Scholar]
- Yokota H., Yuasa A. Increase of a form of UDP-glucuronyltransferase glucuronizing various phenolic xenobiotics and the corresponding translatable mRNA in 3-methylcholanthrene-treated rat liver. J Biochem. 1990 Jan;107(1):92–96. doi: 10.1093/oxfordjournals.jbchem.a123019. [DOI] [PubMed] [Google Scholar]