Role of Selenoprotein P in Male Fertility

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DESCRIPTION (provided by applicant): Selenium is an essential dietary micronutrient required to maintain male fertility. Selenium exerts its physiological activity through selenoproteins that contain stochiometric amounts of selenium, as selenocysteine, in their primary structure. Epididymal spermatozoa of selenium deficient animals exhibit a loss of motility and display various defects including abnormalities of the mitochondrial sheath and disorganization of the flagellar fibers; our studies demonstrate the defects appear sequentially during spermiogenesis and post-testicular maturation underscoring roles for selenium in both the testis and epididymis. Selenium concentrations of the testis and spermatozoa are higher than other tissues, and the testis maintains its selenium content longer than other organs during dietary selenium deficiency. Thus the testis has a mechanism with which it competes effectively for selenium within the animal to support sperm development. Selenoprotein P (Se-P) is an extracellular selenoprotein that accounts for most of the selenium in plasma. We have produced Se-P null mice and the homozygous males are infertile. Testis selenium levels of Se-P null mice are extremely low and not elevated by selenium supplementation. Spermatids and epididymal spermatozoa of Se-P null animals exhibit structural defects of selenium deficiency. Our central hypothesis is that Se-P provides selenium to specific cell types of the testis and epididymis to support selenoprotein synthesis required for normal sperm development. The specific aims of this study are: Aim 1: To elucidate the potential roles of Se-P in spermiogenesis and post-testicular sperm development by defining its localization in the testis and epididymis. Aim 2: To determine if Se-P provides selenium to the seminiferous and epididymal tubules for biosynthesis of other selenoproteins. Aim 3: To identify and localize Se-P-binding proteins in the testis and epididymis. Aim 4: To determine the molecular basis for sperm defects in Se-P null mice.