Sphingomyelin Synthase 1 Is Essential for Male Fertility in Mice

Abstract

Sphingolipids and the derived gangliosides have critical functions in spermatogenesis, thus mutations in genes involved in sphingolipid biogenesis are often associated with male infertility. We have generated a transgenic mouse line carrying an insertion in the sphingomyelin synthase gene Sms1, the enzyme which generates sphingomyelin species in the Golgi apparatus. We describe the spermatogenesis defect of Sms1-/- mice, which is characterized by sloughing of spermatocytes and spermatids, causing progressive infertility of male homozygotes. Lipid profiling revealed a reduction in several long chain unsaturated phosphatidylcholins, lysophosphatidylcholins and sphingolipids in the testes of mutants. Multi-Spectral Optoacoustic Tomography indicated blood-testis barrier dysfunction. A supplementary diet of the essential omega-3 docosahexaenoic acid and eicosapentaenoic acid diminished germ cell sloughing from the seminiferous epithelium and restored spermatogenesis and fertility in 50% of previously infertile mutants. Our findings indicate that SMS1 has a wider than anticipated role in testis polyunsaturated fatty acid homeostasis and for male fertility.

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

“… 105 In the testis of SMS1-KO mice, the levels of SM with several long chain unsaturated PC and lyso-PC were reduced, resulting in male fertility. 106 In our study, the levels of very long chain SMs (C24:1 and C24:0) in the testis were increased, and brain SM levels were significantly decreased in SMS1-KO mice ( Table 1 ). 96 Xue et al 107 have reported that SMS2 deficiency also resulted in decreased SM levels in the mouse brain.…”

“…In addition, a defect in spermatogenesis causing male infertility was found in SMS1-KO male mice. 106 Alterations in SM metabolism by SMS1 deficiency reduced not only SM, but also polyunsaturated PC and lyso-PC. Dysfunction and leakage of blood-testis barrier, which is based on cell-cell junctions and maintains the microenvironment for spermatogenesis at the seminiferous tubule, 112 occurred in SMS1-KO mice due to change in polyunsaturated fatty acid (PUFA) homeostasis.…”

The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA

“…Thus, although the lowest SMS1 expression was about 57%, the highest expression measured in glioma patients (Figure S8), siSMS1 caused a reduction to 10% of the control SMS1 expression in vitro, potentially compromising GBM cell survival. This premise is supported by the fact that SMS1 KO mice show deteriorated growth and male infertility, and they are born in a lower Mendelian ratio [36,37], which indicates the relevance of SMS1 expression during development.…”

Sphingomyelin Synthase 2 Participate in the Regulation of Sperm Motility and Apoptosis

“…Thus, our results suggested that SMS2 may play some role(s) in spermatogenesis. In fact, Wittmann et al also showed similar results for SMS1 in mice, wherein SMS1 plays a wider role in testis polyunsaturated fatty acid homeostasis and in male fertility [ 21 ]. Moreover, when we tested the SMS2 expression in sperm cells, we were able to show that the SMS2 was located mainly on the head and tail of sperm cells.…”

“…In detail, SM can influence the rate of capacitation by slowing the loss of sterols [ 19 ]. Moreover, Lee et al and Wittmann et al suggested that SMS may play a crucial role in sloughing of spermatocytes and spermatids, causing progressive infertility of male homozygotes, acrosome formation, and plasma membrane restructuring from late round spermatids to early elongating spermatids by affecting the lipid metabolism in mice [ 20 , 21 ]. Clearly, SMS are associated with male infertility.…”