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Estrogen Receptor ß-Mediated Inhibition of Male Germ Cell Line Development in Mice by Endogenous Estrogens during Perinatal Life

Unité de Gamétogenèse et Génotoxicité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 566, Commissariat à l’Energie Atomique, Université Paris 7–Denis Diderot (G.D., C.L., C.P., C.R., C.D., R.H.), 92265 Fontenay-aux-Roses; and Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM Unité 184, Centre National de la Recherche Scientifique/INSERM/Université Louis Pasteur, Collège de France (A.K.), BP 163, 37404 Illkirch-Cedex, France

Address all correspondence and requests for reprints to: Dr. Christine Levacher, Institut National de la Santé et de la Recherche Médicale Unité 566, Commissariat à l’Energie Atomique, Université Paris 7–Denis Diderot, DSV/DRR/SEGG/LDRG, Bâtiment 5A, RDC, Route du Panorama, 92265 Fontenay-aux-Roses, France. E-mail: christine.levacher{at}cea.fr.

Epidemiological, clinical, and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders and sperm abnormalities in adulthood. However, it is unknown whether endogenous concentrations of estrogens affect the establishment of the male fetal germ cell lineage. We addressed this question by studying the testicular development of mice in which the estrogen receptor (ER) ß or the ER gene was inactivated. The homozygous inactivation of ERß (ERß–/–) increased the number of gonocytes by 50% in 2- and 6-d-old neonates. The numbers of Sertoli and Leydig cells and the level of testicular testosterone production were unaffected, suggesting that estrogens act directly on the gonocytes. The increase in the number of gonocytes did not occur during fetal life but instead occurred just after birth, when gonocytes resumed mitosis and apoptosis. It seems to result from a decrease in the apoptosis rate evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and cleaved caspase-3 immunohistochemical detection. Last, mice heterozygous for the ERß gene inactivation behaved similarly to their ERß–/– littermates in terms of the number of gonocytes, apoptosis, and mitosis, suggesting that these cells are highly sensitive to the binding of estrogens to ERß. ER inactivation had no effect on the number of neonatal gonocytes and Sertoli cells. In conclusion, this study provides the first demonstration that endogenous estrogens can physiologically inhibit germ cell growth in the male. This finding may have important implications concerning the potential action of environmental estrogens.

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