THE MURINE NIEMANN-PICK TYPE-C LESION AFFECTS TESTOSTERONE PRODUCTION

We have determined the effects of the Niemann-Pick type C (NPC) lesion , which impairs transport of cholesterol from lysosomes, on the androg enic status of male NPC mice. The mice have low serum testosterone lev els resulting from decreased testosterone secretion. Testosterone secr etion is reduced in NPC mouse testes incubated with 8-bromo-cAMP, 20al pha-hydroxycholesterol, and pregnenolone compared to testosterone rele ase by normal mouse testes under identical conditions. Ultrastuctural examination of testes revealed a paucity of lipid droplets, extensive accumulation of inclusion bodies, and distorted endoplasmic reticulum in Leydig cells of adult NPC mice. The hypoandrogenemia caused systemi c deficiencies in NPC mice. Seminal vesicles, a testosterone-responsiv e tissue, were underdeveloped in NPC male mice. The testosterone-respo nsive kidney beta-glucuronidase activity was also underexpressed. Semi nal vesicle mass and beta-glucuronidase activity were increased by tes tosterone treatment of NPC mice. Many hepatic proteins, identified by microsequencing, were also deficient in NPC male mice. Levels of alpha 2-mu-globulin, glutathione S-transferase-pi, carbonic anhydrase-III, a nd selenium-binding protein increased in normal male mice during puber ty, but did not increase in the NPC male mice. Based on the increases in protein expression during puberty, differential expression in males and females, and the reported involvement of androgens in regulating expression of some of these proteins, deficient expression of most of these proteins in male NPC mice appears to result from low testosteron e levels. We conclude that a defect in testicular testosterone product ion in NPC male mice causes a pleiotropic deficiency in androgen-sensi tive expression of proteins in various organs.