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Androgens and Postmeiotic Germ Cells Regulate Claudin-11 Expression in Rat Sertoli Cells

Institut National de la Santé et de la Recherche Médicale, Unité 407, Oullins F-69921; Faculté de Médecine Lyon-Sud (A.F., M.M., A.B., A.H., S.C., M.B.), Lyon F-69921, France; BayerCorpScience (R.B.), Sophia-Antipolis F-06903; and Galderma (F.C.), Sophia-Antipolis F-06560, France

Address all correspondence and requests for reprints to: Dr. 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 the present study we investigated whether fetal exposure to flutamide affected messenger and protein levels of claudin-11, a key Sertoli cell factor in the establishment of the hemotesticular barrier, at the time of two key events of postnatal testis development: 1) before puberty (postnatal d 14) during the establishment of the hemotesticular barrier, and 2) at the adult age (postnatal d 90) at the time of full spermatogenesis. The data obtained show that claudin-11 expression was inhibited in prepubertal rat testes exposed in utero to 2 and 10 mg/kg·d flutamide. However, in adult testes, the inhibition was observed only with 2, and not with 10, mg/kg·d of the antiandrogen. It is shown here that these differences between prepubertal and adult testes could be related to dual and opposed regulation of claudin-11 expression resulting from positive control by androgens and an inhibitory effect of postmeiotic germ cells. Indeed, testosterone is shown to stimulate claudin-11 expression in cultured Sertoli cells in a dose- and time-dependent manner (maximum effect with 0.06 µM after 72 h of treatment). In contrast, postmeiotic germ cells potentially exert a negative effect on claudin-11 expression, because adult rat testes depleted in spermatids (after local irradiation) displayed increased claudin-11 expression, whereas in a model of cocultured Sertoli and germ cells, spermatids, but not spermatocytes, inhibited claudin-11 expression. The apparent absence of claudin-11 expression changes in adult rat testes exposed to 10 mg/kg·d flutamide therefore could result from the antagonistic effects of 1) the inhibitory action of the antiandrogen and 2) the stimulatory effect of the apoptotic germ cells on claudin-11 expression. Together, due to the key role of claudin-11 in the hemotesticular barrier, the present findings suggest that such regulatory mechanisms may potentially affect this barrier (re)modeling during spermatogenesis.

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