Testis

Signaling Pathways for Germ Cell Death in Adult Cynomolgus Monkeys (Macaca fascicularis) Induced by Mild Testicular Hyperthermia and Exogenous Testosterone Treatment

Abstract
Male contraception has focused to a great extent on approaches that induce azoospermia or severe oligospermia through accelerated germ cell apoptosis. Understanding the specific steps in the germ cell apoptotic pathways that are affected by male contraceptives will allow more specific targeting in future contraceptive development. In this study, we have used a nonhuman primate model to characterize the key apoptotic pathway(s) in germ cell death after mild testicular hyperthermia, hormonal deprivation, or after combined interventions. Groups of 8 adult (7 to 10 years old) Cynomolgus monkeys (Macaca fascicularis) received one of the following treatments: 1) two empty silastic implants; 2) two 5.5 cm-testosterone (T) implants; 3) daily exposure of testes to heat (43C for 30 min) for 2 consecutive days; and 4) two T-implants plus testicular heat exposure for 2 consecutive days. Testicular biopsies were performed before and at 3, 8, and 28 days during treatment. Treatment with T, heat, or both led to sustained activation of both mitogen-activated protein kinase (MAPK) 1/3 and MAPK14. Activation of MAPK1/3 and MAPK14 were accompanied by an increase in BCL2 levels in both cytosolic and mitochondrial fractions of testicular lysates (BAX levels remained unaffected) and cytochrome c and DIABLO release from mitochondria. These treatments also resulted inactivation of BCL2 through phosphorylation at serine 70, thereby favoring the death pathway. We conclude that the serine phosphorylation of BCL2 and activation of the MAPK14-mediated mitochondria-dependent pathway are critical for male germ cell death in monkeys.

Key words: Testis • Apoptosis • Spermatogenesis

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