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Alteration of Transforming Growth Factor-ß Signaling System Expression in Adult Rat Germ Cells with a Chronic Apoptotic Cell Death Process after Fetal Androgen Disruption

Institut National de la Santé et de la Recherche Médicale, Unité 407 (M.M., A.F. K.K., D.R., P.C., E.T., C.M., M.B.), Faculté de Médecine Lyon-Sud, 69921 Oullins, France; and BayerCropScience (R.B), Sophia-Antipolis F-06903, France

Address all correspondence and requests for reprints to: Mohamed Benahmed, Institut National de la Santé et de la Recherche Médicale Unité 407, Faculté de Médecine Lyon-Sud, BP 12, 69921 Oullins Cedex-France. E-mail: benahmed{at}grisn.univ-lyon1.fr.

In utero exposure to chemicals with antiandrogen activity induces undescended testis, hypospadias, and sub- or infertility. The hypospermatogenesis observed in the adult rat testis exposed in utero to the antiandrogen flutamide has been reported to be a result of a long-term apoptotic cell death process in mature germ cells. However, little if anything is known about the upstream signaling mechanisms controlling this apoptosis. In the present study, we have investigated the possibility that the TGF-ß signaling pathway may be at play in this control of the apoptotic germ cell death process. By using a model of adult rat exposed in utero to 0, 0.4, 2, or 10 mg/kg·d flutamide, we observed that pro-TGF-ß signaling members, such as the three isoforms of TGF-ß ligands (TGF-ß1–3), the two TGF-ß receptors (TGF-ßRI and -RII) and the R-Smads Smad 1, Smad 2, Smad 3, and Smad 5 were inhibited at the mRNA and protein levels, whereas the anti-TGF-ß signaling member Smad 7 was overexpressed. Furthermore, we report that the overexpression of Smad 7 mRNA could induce an activation of c-Jun N-terminal kinase, because of the observed c-Jun overexpression, activation, and nuclear translocation leading to an increase in the transcription of the proapoptotic factor Fas-L. Together, the alterations of TGF-ß signaling may represent upstream mechanisms underlying the adult germ cell apoptotic process evidenced in adult rat testis exposed in utero to antiandrogenic compounds such as flutamide.

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				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]