Testis

Effects of Acid Sphingomyelinase Deficiency on Male Germ Cell Development and Programmed Cell Death

Abstract
Deficiency of acid sphingomyelinase (ASM), an enzyme responsible for producing a pro-apoptotic second messenger ceramide, has previously been shown to promote the survival of fetal mouse oocytes in vivo and to protect oocytes from chemotherapy-induced apoptosis in vitro. Here, we investigated the effects of ASM deficiency on testicular germ cell development and on the ability of germ cells to undergo apoptosis. At the age of 20 weeks ASMKO sperm concentrations were comparable to WT sperm concentrations, whereas sperm motility was seriously affected. Acid sphingomyelinase knock-out (ASMKO) testes contained significantly elevated levels of sphingomyelin at the age of 8 weeks, as detected by high performance thin-layer chromatography. Electron microscopy revealed that the testes started to accumulate pathological vesicles in Sertoli cells and in the interstitium at the age of 21 d. Irradiation of WT and ASMKO mice did not elevate intratesticular ceramide levels at 16 hours after irradiation. In situ-end labeling of apoptotic cells also showed similar degree of cell death in both groups. After a 21-day recovery period the numbers of primary spermatocytes and spermatogonia at G2 as well as spermatids were essentially same in the WT and ASMKO testes, as detected by flow cytometry. In serum-free cultures both ASMKO and WT germ cells showed significant increase in the level of ceramide, as well as massive apoptosis. In conclusion, ASM is required for maintenance of normal sphingomyelin levels in the testis and for normal sperm motility, but not for testicular ceramide production or for the ability of the germ cells to undergo apoptosis.

Key words: Testis • Apoptosis • Spermatogenesis • Stress

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