In utero exposure to chemicals with antiandrogen activity induces undescended testis, hypospadias and sub(in)fertility. The hypospermatogenesis observed in the adult rat testis exposed in utero to the antiandrogen flutamide has been reported to be due to a long-term apoptotic cell death process in mature germ cells. However, little if nothing is known about the upstream signaling mechanisms controlling this apoptosis. In the present study, we have investigated the possibility that the Transforming Growth Factor (TGF-) 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 to 10 mg/kg.d of flutamide, we observed that pro-TGF- signaling members, such as the three isoforms of TGF- ligands (TGF- 1-3), the two TGF- receptors (TGF- RI and RII) and the R-Smads Smad 1, Smad 2, Smad 3, and Smad 5 were inhibited at the mRNA and protein levels, while the anti-TGF- signaling member Smad 7 was over expressed. Furthermore, we report that the over expression of Smad 7 mRNA could induce an activation of JNK, because of the observed c-Jun over expression, activation and nuclear translocation leading to an increase in the transcription of the pro-apoptotic factor Fas-L. Together, the alterations of TGF- 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.