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 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 degrees 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.

• Authors: Yue Jia, Amiya P Sinha Hikim, Yan-He Lue, Ronald S Swerdloff, Yanira Vera, Xue-Shen Zhang, Zhao-Yuan Hu, Yin-Chuan Li, Yi-Xun Liu, Christina Wang
• Journal: Biology of reproduction (Biol Reprod) Vol. 77 Issue 1 Pg. 83-92 (Jul 2007) ISSN: 0006-3363 [Print] United States
• PMID: 17377139 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Testosterone
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Germ Cells (cytology, drug effects, metabolism)
• Hot Temperature
• Macaca fascicularis
• Male
• Mitochondria (metabolism)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Signal Transduction
• Testis (cytology, drug effects, metabolism)
• Testosterone (pharmacology)