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Sphingosine-1-Phosphate in Inhibition of Male Germ Cell Apoptosis in the Human Testis

Programme for Developmental and Reproductive Biology, Biomedicum Helsinki, and Hospital for Children and Adolescents, University of Helsinki (L.S., V.P., K.E., M.O., L.D.), FIN-00029 Helsinki, Finland; and Wihuri Research Institute (J.K.H., M.O.P.), FIN-00140 Helsinki, Finland

Address all correspondence and requests for reprints to: Laura Suomalainen, M.D., Hospital for Children and Adolescents, University of Helsinki, Biomedicum, Helsinki, Haartmaninkatu 8, B529b, P.O. Box 700, FIN-00029, Helsinki, Finland. E-mail: laura.suomalainen{at}hus.fi.

It has been suggested that apoptosis is controlled by two intracellular sphingolipids, ceramide and sphingosine-1-phosphate (S1P), which are widely distributed in mammalian tissues. In the ovary, S1P was found to effectively block apoptosis caused by cancer therapies. Its role in male germ cell death, however, was unknown. In this study, we investigated the effects of ceramide and S1P on human male germ cell apoptosis. Germ cell death was induced by incubation of segments of seminiferous tubules in vitro. During apoptosis, ceramide levels increased rapidly before appearance of caspase 3 activation and DNA laddering, suggesting a role for ceramide in the induction of germ cell death. Ceramide appeared to regulate an early step of apoptosis because n-acetyl-L-cysteine and blockade of mitochondrial respiration inhibited apoptosis but had no effect on ceramide levels. Moreover, fumonisin B1 (ceramide synthetase inhibitor) did not significantly affect testicular apoptosis. Therefore, elevated ceramide levels are likely to result from breakdown of sphingomyelin rather than from de novo synthesis. Finally, we found that S1P at 1 and 10 µmol/liter suppressed germ cell apoptosis by 30% (P < 0.001). Taken together, sphingolipids appear to play a role in male germ cell apoptosis and can partly be inhibited by S1P.

This work was supported by the Foundation for Pediatric Research, the Sigrid Juselius Foundation, and Pediatric Graduate School, University of Helsinki, Finland.

Abbreviations: ASMase, Acid sphingomyelinase; Dig-dd-UTP, digoxigenin-dideoxy-UTP; FB1, fumonisin B1; HPTLC, high-performance thin-layer chromatography; ISEL, in situ end labeling; KCN, potassium cyanide; NAC, n-acetyl-L-cysteine; NSMase, neutral sphingomyelinase; S1P, sphingosine-1-phosphate.

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