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Effects of Acid Sphingomyelinase Deficiency on Male Germ Cell Development and Programmed Cell Death¹

Program for Developmental and Reproductive Biology,³ Biomedicum Helsinki and Hospital for Children and Adolescents, University of Helsinki, FIN-00029 HUS, Helsinki, Finland Wihuri Research Institute,⁴ FIN-00140, Helsinki, Finland Vincent Center for Reproductive Biology,⁵ Vincent Obstetrics and Gynecology Service, Massachusetts General Hospital, and Department of Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02114 Department of Oncology,⁶ Helsinki University Hospital, FIN-00029, Helsinki, Finland Department of Anatomy,⁷ University of Turku, FIN-20520 Turku, Finland Department of Pediatrics,⁸ University of Kuopio, FIN-70211, Kuopio, Finland

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, ASM knock-out (ASMKO) sperm concentrations were comparable with wild-type (WT) sperm concentrations, whereas sperm motility was seriously affected. 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 days. Irradiation of WT and ASMKO mice did not elevate intratesticular ceramide levels at 16 h after irradiation. In situ end labeling of apoptotic cells also showed a 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 the same in the WT and ASMKO testes, as detected by flow cytometry. In serum-free cultures both ASMKO and WT germ cells showed a 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.

¹ Supported by the Sigrid Jusélius Foundation (Finland), the Cancer Society of Finland, the Nona and Kullervo Väre Foundation (Finland), Helsinki Biomedical Graduate School (Finland), the Finnish Foundation for Pediatric Research, the Finnish Cultural Foundation, and the Research and Science Foundation of Farmos (Finland).

² Correspondence: Marjut Otala, Program for Developmental and Reproductive Biology (5th Floor, Room B529b), Biomedicum Helsinki, University of Helsinki, P.O. Box 700, FIN-00029 HUS, Helsinki, Finland. FAX: 35 894 717 1947; marjut.otala{at}hus.fi

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