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. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044863-05
Application #
7236227
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Rankin, Tracy L
Project Start
2003-06-06
Project End
2008-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
5
Fiscal Year
2007
Total Cost
$289,931
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Olson, Gary E; Winfrey, Virginia P; Hill, Kristina E et al. (2008) Megalin mediates selenoprotein P uptake by kidney proximal tubule epithelial cells. J Biol Chem 283:6854-60
Burk, Raymond F; Hill, Kristina E; Olson, Gary E et al. (2007) Deletion of apolipoprotein E receptor-2 in mice lowers brain selenium and causes severe neurological dysfunction and death when a low-selenium diet is fed. J Neurosci 27:6207-11
Olson, Gary E; Winfrey, Virginia P; Nagdas, Subir K et al. (2007) Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein P by the mouse testis. J Biol Chem 282:12290-7
Hill, Kristina E; Zhou, Jiadong; Austin, Lori M et al. (2007) The selenium-rich C-terminal domain of mouse selenoprotein P is necessary for the supply of selenium to brain and testis but not for the maintenance of whole body selenium. J Biol Chem 282:10972-80