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Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology (N.A., C.M., M.W., K.J.T., J.S.F., M.M., M.R.M., R.M.S.), Edinburgh, Scotland EH3 9ET; the Institute of Experimental Morphology and Anthropology, Bulgarian Academy of Science (N.A.), 1113 Sofia, Bulgaria; the School of Biological and Molecular Sciences, Oxford Brookes University (N.P.G.), Headington, Oxford, United Kingdom OX3 0BP
Address all correspondence and requests for reprints to: Dr. R. M. Sharpe, Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology, 37 Chalmers Street, Edinburgh, Scotland EH3 9ET. E-mail: r.sharpe{at}ed-rbu.mrc.ac.uk
This study aimed to identify the mechanism(s) for impairment of spermatogenesis in adulthood in rats treated neonatally with estrogens. Rats were treated (days 2–12) with 10, 1, or 0.1 µg diethylstilbestrol (DES), 10 µg ethinyl estradiol (EE), 10 mg/kg of a GnRH antagonist (GnRHa), or vehicle and killed in adulthood. DES/EE caused dose-dependent reductions in testis weight, total germ cell volume per testis, and Sertoli cell volume per testis. Sertoli cell number at 18 days of age in DES-treated rats was reduced dose dependently. GnRHa treatment caused changes in these parameters similar to those in rats treated with 10 µg DES. Plasma FSH levels were elevated (P < 0.001) to similar levels in all treatment groups regardless of differences in Sertoli cell number and levels of inhibin B; the latter reflected Sertoli cell number, but levels were disproportionately reduced in animals treated with high doses of DES/EE. Neonatal estrogen treatment, but not GnRHa, caused dose-dependent reductions (40–80%) in plasma testosterone levels in adulthood, but did not alter LH levels. Preliminary evidence suggests that the decrease in testosterone levels in estrogen-treated rats is not due to reduced Leydig cell volume per testis.
GnRHa-treated rats exhibited a significant increase in germ cell volume per Sertoli cell and a reduction in germ cell apoptosis, probably because of the raised FSH levels. Despite similar raised FSH levels, rats treated with DES (10 or 1 µg) or EE (10 µg) had reduced germ cell volume/Sertoli cell and increased germ cell apoptosis, especially when compared with GnRHa-treated animals. The latter changes were associated with an increase in lumen size per testis, indicative of impaired fluid resorption from the efferent ducts, resulting in fluid accumulation in the testis. Rats treated neonatally with 0.1 µg DES showed reduced germ cell apoptosis comparable to that in GnRHa-treated animals. The changes in apoptotic rate among treatment groups occurred across all stages of the spermatogenic cycle. It is concluded that 1) neonatal estrogen treatment results in dose-dependent alterations in Sertoli cell numbers, germ cell volume, efficiency of spermatogenesis, and germ cell apoptosis in adulthood; 2) the relatively poor spermatogenesis in estrogen-treated animals is most likely due to altered testis fluid dynamics and/or altered Sertoli cell function; 3) as indicated by FSH (LH) and testosterone levels, the hypothalamic-pituitary axis and Leydig cells are probably more sensitive than the Sertoli cells to reprogramming by estrogens neonatally; and 4) elevated FSH levels in adulthood may improve the efficiency of spermatogenesis.
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A. Rivas, J. S. Fisher, C. McKinnell, N. Atanassova, and R. M. Sharpe 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 Endocrinology, December 1, 2002; 143(12): 4797 - 4808. [Abstract] [Full Text] [PDF]
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J. S. Fisher, N. Pastor-Soler, R. M. Sharpe, and S. Breton Modulation of the Onset of Postnatal Development of H+-ATPase-Rich Cells by Steroid Hormones in Rat Epididymis Biol Reprod, October 1, 2002; 67(4): 1106 - 1114. [Abstract] [Full Text] [PDF]
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K. M. Robertson, L. O'Donnell, E. R. Simpson, and M. E. E. Jones The Phenotype of the Aromatase Knockout Mouse Reveals Dietary Phytoestrogens Impact Significantly on Testis Function Endocrinology, August 1, 2002; 143(8): 2913 - 2921. [Abstract] [Full Text] [PDF]
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M. R. Fielden, R. G. Halgren, C. J. Fong, C. Staub, L. Johnson, K. Chou, and T. R. Zacharewski Gestational and Lactational Exposure of Male Mice to Diethylstilbestrol Causes Long-Term Effects on the Testis, Sperm Fertilizing Ability in Vitro, and Testicular Gene Expression Endocrinology, August 1, 2002; 143(8): 3044 - 3059. [Abstract] [Full Text] [PDF]
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R. M. Sharpe, B. Martin, K. Morris, I. Greig, C. McKinnell, A. S. McNeilly, and M. Walker Infant feeding with soy formula milk: effects on the testis and on blood testosterone levels in marmoset monkeys during the period of neonatal testicular activity Hum. Reprod., July 1, 2002; 17(7): 1692 - 1703. [Abstract] [Full Text] [PDF]
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C.J.H. Kelnar, C. McKinnell, M. Walker, K.D. Morris, W.H.B. Wallace, P.T.K. Saunders, H.M. Fraser, and R.M. Sharpe Testicular changes during infantile 'quiescence' in the marmoset and their gonadotrophin dependence: a model for investigating susceptibility of the prepubertal human testis to cancer therapy? Hum. Reprod., May 1, 2002; 17(5): 1367 - 1378. [Abstract] [Full Text] [PDF]
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 D. T. Solum and R. J. Handa Estrogen Regulates the Development of Brain-Derived Neurotrophic Factor mRNA and Protein in the Rat Hippocampus J. Neurosci., April 1, 2002; 22(7): 2650 - 2659. [Abstract] [Full Text] [PDF]
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O. Putz, C. B. Schwartz, S. Kim, G. A. LeBlanc, R. L. Cooper, and G. S. Prins Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: I. Effects on the Prostate Gland Biol Reprod, November 1, 2001; 65(5): 1496 - 1505. [Abstract] [Full Text] [PDF]
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O. Putz, C. B. Schwartz, G. A. LeBlanc, R. L. Cooper, and G. S. Prins Neonatal Low- and High-Dose Exposure to Estradiol Benzoate in the Male Rat: II. Effects on Male Puberty and the Reproductive Tract Biol Reprod, November 1, 2001; 65(5): 1506 - 1517. [Abstract] [Full Text] [PDF]
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 S. Nilsson, S. Makela, E. Treuter, M. Tujague, J. Thomsen, G. Andersson, E. Enmark, K. Pettersson, M. Warner, and J.-A. Gustafsson Mechanisms of Estrogen Action Physiol Rev, October 1, 2001; 81(4): 1535 - 1565. [Abstract] [Full Text] [PDF]
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 L. O'Donnell, K. M. Robertson, M. E. Jones, and E. R. Simpson Estrogen and Spermatogenesis Endocr. Rev., June 1, 2001; 22(3): 289 - 318. [Abstract] [Full Text] [PDF]
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 H. Nejaty, M. Lacey, and S. A. Whitehead Differing Effects of Endocrine-Disrupting Chemicals on Basal and FSH-Stimulated Progesterone Production in Rat Granulosa-Luteal Cells Experimental Biology and Medicine, June 1, 2001; 226(6): 570 - 576. [Abstract] [Full Text] [PDF]
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 P. T.K. Saunders, R. M. Sharpe, K. Williams, S. Macpherson, H. Urquart, D.S. Irvine, and M. R. Millar Differential expression of oestrogen receptor {{alpha}} and {beta} proteins in the testes and male reproductive system of human and non-human primates Mol. Hum. Reprod., March 1, 2001; 7(3): 227 - 236. [Abstract] [Full Text] [PDF]
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N. Atanassova, C. McKinnell, K. J. Turner, M. Walker, J. S. Fisher, M. Morley, M. R. Millar, N. P. Groome, and R. M. Sharpe Comparative Effects of Neonatal Exposure of Male Rats to Potent and Weak (Environmental) Estrogens on Spermatogenesis at Puberty and the Relationship to Adult Testis Size and Fertility: Evidence for Stimulatory Effects of Low Estrogen Levels Endocrinology, October 1, 2000; 141(10): 3898 - 3907. [Abstract] [Full Text] [PDF]
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R.M. Sharpe, M. Walker, M.R. Millar, N. Atanassova, K. Morris, C. McKinnell, P.T.K. Saunders, and H.M. Fraser Effect of Neonatal Gonadotropin-Releasing Hormone Antagonist Administration on Sertoli Cell Number and Testicular Development in the Marmoset: Comparison with the Rat Biol Reprod, June 1, 2000; 62(6): 1685 - 1693. [Abstract] [Full Text]
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