ToxSci Advance Access published online on March 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg065
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 GERM-INSERM U.435, Université de Rennes I, Campus de Beaulieu, 35042 Rennes cedex, Bretagne, France
* To whom correspondence should be addressed. E-mail: Bernard.jegou{at}rennes.inserm.fr.
The mechanisms underlying the action of estrogens in the fetal testis are still largely obscure. In particular, whether this action is direct or indirect remains largely unexplored. This study aimed at investigating the effect of estradiol (E2) and diethylstilbestrol (DES) on the testis from 14.5-day-old rat fetuses in culture, at concentrations ranging from 4x10-10 M (Kd of E2 for the estrogen receptors (ER): 1-4x10-10 M), to 4x10-6 M (concentration previously shown in the literature to affect in vitro gonocyte proliferation). Exposure to DES and E2 decreased gonocyte number, the effects of DES being much more drastic than those of E2. Gonocyte number decreased in a concentration-dependent manner (day 3: -5%, -16% and -80% at 4x10-10 M, 4x10-8 M and 4x10-6M of DES, respectively), as well as in a time-dependent manner (at 4 x 10-6 M DES: -31% on day 1, -60% on day 2 and -80% on day 3). This was due to a decrease in the gonocyte mitotic index and a dramatic increase in apoptosis. Importantly, in the presence of the anti-estrogen ICI 182.780 (ICI), the effect of DES was abolished. Sertoli cell number subsequently decreased (day 3), although the rate of apoptosis did not increase. These changes were less dramatic than those observed with gonocytes and were due to a decrease in Sertoli cell proliferation, which was not antagonized by ICI. Addition of 4x10-6 M DES had no effect on basal Sertoli cell cAMP levels or on FSH-stimulated cAMP production after adjustment for Sertoli cell number. Finally, estrogens reduced both Leydig cell number (-26% on day 3, 4x10-6 M DES) and basal and LH-stimulated testosterone production. The latter effects were antagonized by ICI. In conclusion: 1) E2 and DES induce alterations in the germ line and in somatic cells. 2) Gonocyte alteration was the first event detected and the action of estrogens at this level was mediated by ER, as is the case in Leydig cells. 3) These data should help us to understand estrogen effects on the fetus and should be considered in the context of the debate on environmental estrogens.
© 2003 Society of Toxicology
Reproductive and Developmental Toxicology
Time- and Dose-Related Effects of Estradiol and Diethylstilbestrol on the Morphology and Function of the Fetal Rat Testis in Culture
2 INSERM-CEA U.566, Université Paris 7, Bat 5 du DRR, BP6, 92265 Fontenay-aux- Roses Cedex, France
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