This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morán, F. M. Articles by Conley, A. J. Search for Related Content PubMed PubMed Citation Articles by Morán, F. M. Articles by Conley, A. J.

Molecular Target of Endocrine Disruption in Human Luteinizing Granulosa Cells by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin: Inhibition of Estradiol Secretion Due to Decreased 17-Hydroxylase/17,20-Lyase Cytochrome P450 Expression

Department of Population Health and Reproduction, School of Veterinary Medicine (F.M.M., A.J.C.), California Regional Primate Research Center (C.A.V.V.), and Center for Health and the Environment (J.W.O., B.L.L.), University of California, Davis, California 95616

Address all correspondence and requests for reprints to: Dr. Alan Conley, Veterinary Medicine, Population Health and Reproduction, University of California, One Shields Avenue, Davis, California 95616-8615. E-mail: ajconley{at}ucdavis.edu.

Estradiol (E2) production by human luteinized granulosa cells (hLGC) is inhibited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The molecular target of TCDD toxicity has not been identified. The decrease in E2 is ameliorated by androgen substrate addition and is not associated with changes in aromatase cytochrome P450 (P450arom) activity or protein expression. An antihuman 17-hydroxylase/17,20-lyase cytochrome P450 (P450c17) antisera and a direct radiometric assay of 17,20-lyase activity were used to test the hypothesis that TCDD targets P450c17, thereby decreasing substrate availability for E2 synthesis by hLGC. P450c17 expression and 17,20-lyase activity were detected in hLGC with high levels of E2 secretion. Western immunoblot analysis demonstrated that TCDD treatment of hLGC decreased the expression of P450c17 by as much 50% (P < 0.05). TCDD exposure induced a 65% decrease in 17,20-lyase activity (P < 0.05), but no changes were seen in P450arom or in nicotinamide adenine dinucleotide phosphate (reduced)-cytochrome P450 oxidoreductase (reductase). Furthermore, the decreases in P450c17 and 17,20-lyase were proportional to the inhibition of E2 secretion. We conclude that the molecular target for endocrine disruption of hLGC by TCDD is P450c17, specifically decreasing the supply of androgens for E2 synthesis, and that it does not involve either P450arom or the redox partner protein reductase.

This article has been cited by other articles:

				J. T. Sanderson The Steroid Hormone Biosynthesis Pathway as a Target for Endocrine-Disrupting Chemicals Toxicol. Sci., November 1, 2006; 94(1): 3 - 21. [Abstract] [Full Text] [PDF]

				K. N. Fru, C. A. VandeVoort, and C. L. Chaffin Mineralocorticoid Synthesis During the Periovulatory Interval in Macaques Biol Reprod, October 1, 2006; 75(4): 568 - 574. [Abstract] [Full Text] [PDF]

				S. A. Myllymaki, T. E. Haavisto, L. J. S. Brokken, M. Viluksela, J. Toppari, and J. Paranko In Utero and Lactational Exposure to TCDD; Steroidogenic Outcomes Differ in Male and Female Rat Pups Toxicol. Sci., December 1, 2005; 88(2): 534 - 544. [Abstract] [Full Text] [PDF]

				L.-A. Li and P.-W. Wang PCB126 Induces Differential Changes in Androgen, Cortisol, and Aldosterone Biosynthesis in Human Adrenocortical H295R Cells Toxicol. Sci., May 1, 2005; 85(1): 530 - 540. [Abstract] [Full Text] [PDF]

				A. H. Payne and D. B. Hales Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones Endocr. Rev., December 1, 2004; 25(6): 947 - 970. [Abstract] [Full Text] [PDF]

				B.-M. Huang, K.-Y. Hsiao, P.-C. Chuang, M.-H. Wu, H.-A. Pan, and S.-J. Tsai Upregulation of Steroidogenic Enzymes and Ovarian 17{beta}-Estradiol in Human Granulosa-Lutein Cells by Cordyceps sinensis Mycelium Biol Reprod, May 1, 2004; 70(5): 1358 - 1364. [Abstract] [Full Text] [PDF]