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Involvement of p38 Mitogen-Activated Protein Kinase and Inducible Nitric Oxide Synthase in Apoptotic Signaling of Murine and Human Male Germ Cells after Hormone Deprivation

Division of Endocrinology (Y.V., K.E., C.W., C.N., Y.L., R.S.S., A.P.S.H.), Department of Medicine, Harbor-University of California at Los Angeles (UCLA) Medical Center and Los Angeles Biomedical Research Institute, David Geffen School of Medicine at UCLA, Torrance, California 90509; Program for Developmental and Reproductive Biology (K.E., S.K., L.D.), Biomedicum Helsinki, and Hospital for Children and Adolescents, University of Helsinki, FIN-00029, Helsinki, Finland; and Department of Pediatrics (L.D.), Kuopio University Hospital, FIN-70211, Kuopio, Finland

Address all correspondence and requests for reprints to: Amiya P. Sinha Hikim, Division of Endocrinology, Harbor-University of California at Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Box 446, 1000 West Carson Street, Torrance, California 90509. E-mail: hikim{at}labiomed.org.

This study investigates the role of p38 MAPK, inducible nitric oxide synthase (iNOS), and the intrinsic pathway signaling in male germ cell death in rats after hormonal deprivation by a potent GnRH antagonist treatment. Germ cell apoptosis, involving exclusively middle (VII–VIII) stages, was activated by d 5 after GnRH antagonist treatment. Initiation of germ cell apoptosis was preceded by p38 MAPK activation and induction of iNOS. p38 MAPK activation and iNOS induction were further accompanied by a marked perturbation of the BAX/BCL-2 rheostat, cytochrome c, and DIABLO release from mitochondria, caspase activation, and poly(ADP-ribose) polymerase cleavage. Concomitant administration of aminoguanidine, a selective iNOS inhibitor, significantly prevented hormone deprivation-induced germ cell apoptosis. Inhibitors of iNOS or p38 MAPK were also effective in preventing human male germ cell apoptosis induced by hormone-free culture conditions. Together, these results establish a new signal transduction pathway involving p38 MAPK and iNOS that, through activation of the intrinsic pathway signaling, promotes male germ cell death in response to a lack of hormonal stimulation across species.

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