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 Rivas, A. Articles by Sharpe, R. M. Search for Related Content PubMed PubMed Citation Articles by Rivas, A. Articles by Sharpe, R. M.

Induction of Reproductive Tract Developmental Abnormalities in the Male Rat by Lowering Androgen Production or Action in Combination with a Low Dose of Diethylstilbestrol: Evidence for Importance of the Androgen-Estrogen Balance

Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, University of Edinburgh Academic Center (A.R., J.S.F., C.M., R.M.S.), Edinburgh, United Kingdom EH16 4SB; and Institute of Experimental Morphology and Anthropology, Bulgarian Academy of Science (N.A.), 1113 Sofia, Bulgaria

Address all correspondence and requests for reprints to: Dr. Richard M. Sharpe, Medical Research Council Human Reproductive Sciences Unit, Center for Reproductive Biology, 49 Little France Crescent, Old Dalkeith Road, University of Edinburgh Academic Center, Edinburgh, United Kingdom EH16 4SB. E-mail: r.sharpe{at}hrsu.mrc.ac.uk.

This study tested the hypothesis that testis/reproductive tract abnormalities induced in the rat by neonatal treatment with diethylstilbestrol (DES) result from disturbance of the androgen-estrogen balance. Male rats were treated neonatally with a dose of DES (0.1 µg) that induced either no or small effects on its own or with a dose (10 µg) that induced major reproductive tract abnormalities. To allow quantification, the abnormalities chosen for study were distension of the rete testis and efferent ducts and reduction in epithelial cell height in the efferent ducts and vas deferens. To alter the androgen-estrogen balance, other rats were treated with DES (0.1 µg) in combination with a treatment to suppress either androgen production [GnRH antagonist (GnRHa)] or androgen action (flutamide); other rats were treated with GnRHa or flutamide alone. Testosterone levels were measured to verify the effects of treatment. Combined administration of DES (0.1 µg) plus GnRHa or flutamide induced significantly greater distension/overgrowth of the rete testis and efferent ducts (ED) and a reduction in epithelial cell height of the ED than did DES (0.1 µg) administered alone. Neither GnRHa nor flutamide affected rete or ED distension when administered alone, but both significantly reduced ED epithelial cell height. Neonatal treatment with bisphenol-A (100 µg) with or without GnRHa had no significant effect on any of these parameters. In contrast to the ED, a reduction in cell height of the vas deferens was induced to an equal extent by DES (10 µg), DES (0.1 µg) with GnRHa, and GnRHa alone, suggesting greater sensitivity of this tissue to both androgen and estrogen action. The induction of major abnormalities in rats treated with DES (10 µg) was coincident with loss of androgen receptor immunoexpression in affected tissues. Reduced androgen receptor immunoexpression was also induced by combined treatment with DES (0.1 µg) plus GnRHa or flutamide, whereas treatment with any of these compounds alone had no or only minor effects. These findings suggest that reduced androgen action sensitizes the reproductive tract to estrogens, demonstrating that the balance in action between androgens and estrogens, rather than their absolute levels, may be of fundamental importance in determining normal or abnormal development of some regions of the male reproductive tract.

This article has been cited by other articles:

				S. J. Liu, J. X. Zheng, and N. Yang Semen Quality Factor as an Indicator of Fertilizing Ability for Geese Poult. Sci., January 1, 2008; 87(1): 155 - 159. [Abstract] [Full Text] [PDF]

				T. F. M. Mikkila, J. Toppari, and J. Paranko Effects of Neonatal Exposure to 4-Tert-Octylphenol, Diethylstilbestrol, and Flutamide on Steroidogenesis in Infantile Rat Testis Toxicol. Sci., June 1, 2006; 91(2): 456 - 466. [Abstract] [Full Text] [PDF]

				J. M. Naciff, K. A. Hess, G. J. Overmann, S. M. Torontali, G. J. Carr, J. P. Tiesman, L. M. Foertsch, B. D. Richardson, J. E. Martinez, and G. P. Daston Gene Expression Changes Induced in the Testis by Transplacental Exposure to High and Low Doses of 17{alpha}-Ethynyl Estradiol, Genistein, or Bisphenol A Toxicol. Sci., August 1, 2005; 86(2): 396 - 416. [Abstract] [Full Text] [PDF]

				D.H. Abbott, D.K. Barnett, C.M. Bruns, and D.A. Dumesic Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum. Reprod. Update, July 1, 2005; 11(4): 357 - 374. [Abstract] [Full Text] [PDF]

				P. M. D. Foster and M. W. Harris Changes in Androgen-Mediated Reproductive Development in Male Rat Offspring Following Exposure to a Single Oral Dose of Flutamide at Different Gestational Ages Toxicol. Sci., June 1, 2005; 85(2): 1024 - 1032. [Abstract] [Full Text] [PDF]

				N. Atanassova, C. McKinnell, J. Fisher, and R. M Sharpe Neonatal treatment of rats with diethylstilboestrol (DES) induces stromal-epithelial abnormalities of the vas deferens and cauda epididymis in adulthood following delayed basal cell development Reproduction, May 1, 2005; 129(5): 589 - 601. [Abstract] [Full Text] [PDF]

				T. B. Hayes Welcome to the Revolution: Integrative Biology and Assessing the Impact of Endocrine Disruptors on Environmental and Public Health Integr. Comp. Biol., April 1, 2005; 45(2): 321 - 329. [Abstract] [Full Text] [PDF]

				N. N Atanassova, M. Walker, C. McKinnell, J. S Fisher, and R. M Sharpe Evidence that androgens and oestrogens, as well as follicle-stimulating hormone, can alter Sertoli cell number in the neonatal rat J. Endocrinol., January 1, 2005; 184(1): 107 - 117. [Abstract] [Full Text] [PDF]

				C. A Oliveira, G. A B Mahecha, K. Carnes, G. S Prins, P. T K Saunders, L. R Franca, and R. A Hess Differential hormonal regulation of estrogen receptors ER{alpha} and ER{beta} and androgen receptor expression in rat efferent ductules Reproduction, July 1, 2004; 128(1): 73 - 86. [Abstract] [Full Text] [PDF]

				J. S Fisher Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome Reproduction, March 1, 2004; 127(3): 305 - 315. [Abstract] [Full Text] [PDF]

				H. Cardenas and W. F. Pope Attenuation of Estrogenic Effects by Dihydrotestosterone in the Pig Uterus Is Associated with Downregulation of the Estrogen Receptors Biol Reprod, February 1, 2004; 70(2): 297 - 302. [Abstract] [Full Text] [PDF]

				A. Rivas, C. Mckinnell, J. S. Fisher, N. Atanassova, K. Williams, and R. M. Sharpe Neonatal Coadministration of Testosterone With Diethylstilbestrol Prevents Diethylstilbestrol Induction of Most Reproductive Tract Abnormalities in Male Rats J Androl, July 1, 2003; 24(4): 557 - 567. [Abstract] [Full Text] [PDF]