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Signaling Pathways for Germ Cell Death in Adult Cynomolgus Monkeys (Macaca fascicularis) Induced by Mild Testicular Hyperthermia and Exogenous Testosterone Treatment¹

Division of Endocrinology,³ Department of Medicine, Harbor-University of California, Los Angeles (UCLA) Medical Center, David Geffen School of Medicine at UCLA, and Los Angeles Biomedical Research Institute, Torrance, California 90509 State Key Laboratory of Reproductive Biology,⁴ Institute of Zoology, Chinese Academy of Science, Beijing 100080, China Department of Endocrinology,⁵ First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

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 combined interventions. Groups of 8 adult (7- to 10-year-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 (43°C for 30 min) for 2 consecutive days; and 4) two T implants plus testicular heat exposure for two consecutive days. Testicular biopsies were performed before and at Days 3, 8, and 28 of 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 B-cell leukemia/lymphoma (BCL) 2 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 in 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.

apoptosis, primate, spermatogenesis, testis

¹Supported by grants from the Mellon Reproductive Biology Center to R.S.S, C.W, Y.H.L, and A.P.S.H., National Institutes of Health grant RO1 HD39293 to A.P.S.H., R.S.S., and C.W., Major Research Plan Project grant 2006 CBOF 1001, "973" project grant 2006 CB 504001, Chinese Academy of Sciences, Chuangxi program grant KSCA2-YW-R-55, and National Nature Science Foundation of China grant 30230190.

Correspondence: ²Christina Wang, General Clinical Research Center, Box 16, Harbor-UCLA Medical Center, 1 000 West Carson St., Torrance, CA 90509-2910. FAX: 310 533 6972; e-mail: wang{at}labiomed.org

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