This Article Full Text Full Text (PDF) 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 Scott, H. M. Articles by Sharpe, R. M. Search for Related Content PubMed PubMed Citation Articles by Scott, H. M. Articles by Sharpe, R. M.

Role of Androgens in Fetal Testis Development and Dysgenesis

Medical Research Council Human Reproductive Sciences Unit (H.M.S., G.R.H., I.K.M., N.H., M.W., R.M.S.), Centre for Reproductive Biology, The Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom; Division of Biochemistry (K.D.G., G.V.), Catholic University of Leuven, B-300 Leuven, Belgium; and Institute of Comparative Medicine (P.O.), University of Glasgow Veterinary School, Glasgow G61 1QH, United Kingdom

Address all correspondence and requests for reprints to: Richard M. Sharpe, Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: r.sharpe{at}hrsu.mrc.ac.uk.

This study sought to establish whether reduced androgen levels/action in the fetal rat testis induced by di(n-butyl) phthalate (DBP) contributes to dysgenetic features, namely reduced Sertoli cell number, occurrence of multinucleated gonocytes (MNG), and Leydig cell aggregation. Pregnant rats were administered treatments or cotreatments designed to manipulate testosterone levels [DBP, testosterone propionate (TP)] or action [flutamide, 7,12-dimethyl-benz[a]anthracene (DMBA)]. The aforementioned end points were analyzed and related to intratesticular testosterone (ITT) levels and peripheral androgen action (anogenital distance). Dysgenetic features were also evaluated in mice with inactivation of the androgen receptor (testicular feminized or ARKO mice). Exposure to DBP alone, or combined with flutamide, DMBA, or TP, resulted in reduced Sertoli cell number and ITT levels, as did exposure to TP alone; coadministration of DBP + TP caused the most severe reduction in both parameters. A positive correlation between ITT levels and Sertoli cell number was found (r = 0.791; P = 0.019). Similarly, exposure to DBP alone, or as a cotreatment, significantly increased occurrence of MNG and Leydig cell aggregation, and these were negatively correlated with ITT levels. Exposure to flutamide or DMBA alone had no significant effect on these dysgenetic end points. These findings suggest that reduced ITT decreases fetal Sertoli cell numbers and might be involved in Leydig cell aggregation and MNG. However, of these three end points, only Sertoli cell number was affected significantly in ARKO/testicular feminized mice with absent androgen action. Therefore, induction of MNG and Leydig cell aggregation might result from DBP-induced effects other than suppression of ITT levels.

This article has been cited by other articles:

				A. Lehraiki, C. Racine, A. Krust, R. Habert, and C. Levacher Phthalates Impair Germ Cell Number in the Mouse Fetal Testis by an Androgen- and Estrogen-Independent Mechanism Toxicol. Sci., October 1, 2009; 111(2): 372 - 382. [Abstract] [Full Text] [PDF]

				C. McKinnell, R. T. Mitchell, M. Walker, K. Morris, C. J.H. Kelnar, W. H. Wallace, and R. M. Sharpe Effect of fetal or neonatal exposure to monobutyl phthalate (MBP) on testicular development and function in the marmoset Hum. Reprod., September 1, 2009; 24(9): 2244 - 2254. [Abstract] [Full Text] [PDF]

				M. Welsh, R. M. Sharpe, M. Walker, L. B. Smith, and P. T. K. Saunders New Insights into the Role of Androgens in Wolffian Duct Stabilization in Male and Female Rodents Endocrinology, May 1, 2009; 150(5): 2472 - 2480. [Abstract] [Full Text] [PDF]

				H. M. Scott, G. R. Hutchison, M. S. Jobling, C. McKinnell, A. J. Drake, and R. M. Sharpe Relationship between Androgen Action in the "Male Programming Window," Fetal Sertoli Cell Number, and Adult Testis Size in the Rat Endocrinology, October 1, 2008; 149(10): 5280 - 5287. [Abstract] [Full Text] [PDF]

				K. J. Johnson, S. M. McCahan, X. Si, L. Campion, R. Herrmann, and J. S. Barthold The orl Rat with Inherited Cryptorchidism Has Increased Susceptibility to the Testicular Effects of In Utero Dibutyl Phthalate Exposure Toxicol. Sci., October 1, 2008; 105(2): 360 - 367. [Abstract] [Full Text] [PDF]

				C. Schell, M. Albrecht, C. Mayer, J. U. Schwarzer, M. B. Frungieri, and A. Mayerhofer Exploring Human Testicular Peritubular Cells: Identification of Secretory Products and Regulation by Tumor Necrosis Factor-{alpha} Endocrinology, April 1, 2008; 149(4): 1678 - 1686. [Abstract] [Full Text] [PDF]

				G. R Hutchison, H. M Scott, M. Walker, C. McKinnell, D. Ferrara, I. K. Mahood, and R. M Sharpe Sertoli Cell Development and Function in an Animal Model of Testicular Dysgenesis Syndrome Biol Reprod, February 1, 2008; 78(2): 352 - 360. [Abstract] [Full Text] [PDF]

				L. Benbrahim-Tallaa, B. Siddeek, A. Bozec, V. Tronchon, A. Florin, C. Friry, E. Tabone, C. Mauduit, and M. Benahmed Alterations of Sertoli cell activity in the long-term testicular germ cell death process induced by fetal androgen disruption J. Endocrinol., January 1, 2008; 196(1): 21 - 31. [Abstract] [Full Text] [PDF]

				K. J Johnson, J. B Hensley, M. D Kelso, D. G Wallace, and K. W Gaido Mapping Gene Expression Changes in the Fetal Rat Testis Following Acute Dibutyl Phthalate Exposure Defines a Complex Temporal Cascade of Responding Cell Types Biol Reprod, December 1, 2007; 77(6): 978 - 989. [Abstract] [Full Text] [PDF]