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This version published online on February 9, 2006
Molecular Endocrinology, doi:10.1210/me.2005-0395
A more recent version of this article appeared on July 1, 2006
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Submitted on September 27, 2005
Accepted on January 30, 2006

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

Yanira Vera, Krista Erkkilä, Christina Wang, Concepcion Nunez, Sauli Kyttänen, Yanhe Lue, Leo Dunkel, Ronald S. Swerdloff, and Amiya P. Sinha Hikim*

Division of Endocrinology, Department of Medicine, Harbor-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, Biomedicum Helsinki, and Hospital for Children and Adolescents, University of Helsinki, FIN-00029, Helsinki, Finland; Department of Pediatrics, Kuopio University Hospital, FIN-70211, Kuopio, Finland

* To whom correspondence should be addressed. E-mail: hikim{at}labiomed.org.

This study investigates the role of p38 mitogen-activated protein kinase (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 (GnRH-A) treatment. Germ cell apoptosis, involving exclusively middle (VII-VIII) stages, was activated by day 5 after GnRH-A 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 (PARP) cleavage. Concomitant administration of aminoguanidine (AG), 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. Taken 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.
Key words: Apoptosis • p38 MAPK • nitric oxide • cytochrome c • germ cells • testis




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