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Is a Major Contributor to Estrogen-Mediated Fetal Testis Dysgenesis and CryptorchidismDepartment of Genetic Medicine and Development (C.R.C., J.-D.V., S.N.), University of Geneva Medical School and Genomics Platform (O.S., P.D.), National Center of Competence in Research Frontiers in Genetic, University of Geneva, 1211 Geneva 4, Switzerland; and Institut de Génétique et de Biologie Moléculaire et Cellulaire and Institut Clinique de la Souris (P.C.), Collège de France, 67404 Illkirch Cedex, France
Address all correspondence and requests for reprints to: Serge Nef, Department of Genetic Medicine and Development University of Geneva Medical School 1, rue Michel-Servet, CH 1211 Geneva 4, Switzerland. E-mail: Serge.Nef{at}medecine.unige.ch.
Failure of the testes to descend into the scrotum (cryptorchidism) is one of the most common birth defects in humans. In utero exposure to estrogens, such as 17β-estradiol (E2) or the synthetic estrogen diethylstilbestrol (DES), down-regulates insulin-like 3 (Insl3) expression in embryonic Leydig cells, which in turn results in cryptorchidism in mice. To identify the molecular mechanism whereby xenoestrogens block Insl3 gene transcription, we performed a microarray analysis of wild-type or estrogen receptor (ER) 
-mutant testes exposed in utero to pharmacological doses of E2 or DES. Six and 31 genes were respectively down-regulated and up-regulated by estrogen exposure (
4-fold). All six genes down-regulated by estrogen exposure, including Insl3 and the steroidogenic genes steroidogenic acute regulatory protein and cytochrome P450 17-hydroxylase/17,20-lyase, were done so by an ER-dependent mechanism. In contrast, up-regulation was mediated either by ER for 12 genes or by an independent mechanism for the 19 remaining genes. Finally, we show that Insl3 gene expression and testicular descent were not affected by in utero exposure to E2 or DES in ER mutant mice, whereas absence of ERβ did not influence the effect of these estrogens. Collectively, these data demonstrate that xenoestrogens inhibit the endocrine functions of fetal Leydig cells through an ER-dependent mechanism.
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