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Involvement of Nitric Oxide-Mediated Intrinsic Pathway Signaling in Age-Related Increase in Germ Cell Apoptosis in Male Brown-Norway Rats

¹ Division of Endocrinology, Department of Medicine
² Division of Urology, Department of Surgery, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, David Geffen School of Medicine at UCLA, Torrance, California.

Address correspondence to Amiya P. Sinha Hikim, PhD, Division of Endocrinology, Box 446, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509. E-mail: hikim{at}gcrc.rei.edu

We examined, using young and old Brown-Norway rats, the involvement of the nitric oxide (NO)-mediated intrinsic pathway signaling in age-related activation of male germ-cell apoptosis. Increased apoptosis of germ cells was readily observed in the normal-looking testes of old rats. Testicular NO synthase (NOS) activity, assessed by measuring the synthesis of ³H-L-citrulline from ³H-L-arginine, and cytokine-inducible NO synthase (iNOS) levels, assessed by western blot assay, were increased significantly by 90% and 70%, respectively, in the old rats compared to that of young animals. Immunohistochemical analysis of age-related changes in the expression of iNOS in testes confirmed our findings based on western blot assay. Increased NO and germ-cell apoptosis during aging is further associated with cytosolic translocation of mitochondrial cytochrome c and poly (ADP) ribose polymerase (PARP) cleavage, thus, suggesting the involvement of NO-mediated intrinsic pathway signaling in age-related increase in germ-cell apoptosis in male Brown-Norway rats.