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Lamia Benbrahim-Tallaa^1,2,*, Bénazir Siddeek^1,2,*, Aline Bozec^1,2,*, Virginie Tronchon^1,2, Anne Florin^1,2, Claire Friry^1,2, Eric Tabone^1,2, Claire Mauduit^1,2,3,

and Mohamed Benahmed^1,2,

¹ Inserm, U407, Oullins F-69921, France ² University Claude Bernard Lyon 1, Lyon F-69921, France ³ Hospices Civils de Lyon, Hôpital Lyon Sud, Service Anatomie Pathologique, Lyon F-69921, France

(Correspondence should be addressed to M Benahmed who is now at INSERM, U895, équipe 5, Bâtiment Archimed, Centre de Médecine Moléculaire, 151 route Saint-Antoine Ginestière, 06200 Nice, France; Email: benahmed.m{at}chu-nice.fr)

^* (L Benbrahim-Tallaa, B Siddeek and A Bozec contributed equally to this work)

(M Benahmed and C Mauduit are the senior co-authors)

Fetal androgen disruption, induced by the administration of anti-androgen flutamide (0.4, 2, and 10 mg/kg day) causes a long-term apoptosis in testicular germ cells in adult male rat offspring. One of the questions raised by this observation is the role of the Sertoli cells in the adult germ cell apoptotic process. It is shown here that Sertoli cells originating from 15-day-old rats treated in utero with the anti-androgen (10 mg/kg d) did no longer protect adult germ cells against apoptosis. Indeed, untreated spermatocytes or spermatids exhibited increased (P<0.0001) active caspase-3 levels when co-cultured with Sertoli cells isolated from rat testes exposed in utero to the anti-androgen. This alteration of Sertoli cell functions was not due to modifications in the androgen signal in the adult (90-day-old) animals, since plasma testosterone and estradiol, androgen receptor expression, and androgen-targeted cell number (e.g., Sertoli cells in the seminiferous tubules) were not affected by the fetal androgen disruption. In contrast, this inability of Sertoli cells to protect germ cells against apoptosis could be accounted for by the potential failure of Sertoli cell functions. Indeed, adult testes exposed in utero to anti-androgens displayed decreased levels of several genes mainly expressed in adult Sertoli cells (anti-Mullerian hormone receptor type II (AMHR2), Cox-1, cyclin D2, cathepsin L, and GST). In conclusion, fetal androgen disruption may induce alterations of Sertoli cell activity probably related to Sertoli cell maturation, which potentially leads to increased adult germ cell apoptosis.