CHARACTERIZATION OF THE TESTIS AND EPIDIDYMIS IN MOUSE MODELS OF HUMAN TAY-SACHS AND SANDHOFF-DISEASES AND PARTIAL DETERMINATION OF ACCUMULATED GANGLIOSIDES

beta-Hexosaminidase (Hex) is an essential lysosomal enzyme whose activ ity is higher in the epididymis than in other tissues. The enzyme is a lso present in sperm and has been postulated to be required for fertil ization. To better understand the role of Hex in reproduction, we have examined the testes and epididymides of mouse models of human Tay Sac hs and Sandhoff diseases, produced by targeted disruption of the Hera (alpha-subunit) or Herb (beta-subunit) genes, respectively, encoding t he enzymes Hex A (structure, alpha beta) and Hex B (beta beta) Testis weight, morphology, and sperm counts were unaffected in Hex-deficient mice. In the epididymis of the Hex A-deficient Hexa -/- mice, there wa s a large increase in the size and number of lysosomes in the initial segment/intermediate zone. In Herb-/- mice (Hex A and B-deficient), th e epididymal defects were much more extensive and the cytoplasm of all cell types throughout the efferent ducts and epididymis was filled wi th pale, uncondensed, enlarged lysosomes. In contrast to the brain whe re G(M2) ganglioside accumulates, both mutant mice accumulated two non -G(M2) gangliosides in the epididymis. The major accumulated species w as characterized by electrospray ionization tandem mass spectrometry. The Hexa -/- male mice were fertile; however, Litter sizes were reduce d. The Hexb-/- males were able to sire normal sized litters up to nine weeks of age and remained healthy until 16-20 weeks of age. The exten sive abnormalities in the Herb -/- mice, in contrast to region-specifi c effects in the Hexa-/- mice, indicate an important and novel role fo r the Hex B isozyme in the epididymis and a region-specific role for H ex A in the initial segment/intermediate zone. In contrast to other re ports, our results indicate that Hex is not essential for fertilizatio n in young adult male mice. To explain the extensive epididymal abnorm alities in the Hexb-/- mice, we propose that substrates for Hex, such as testis-derived glycolipids, cannot be catabolized and accumulate in lysosomes, leading to epididymal dysfunction and abnormalities in the epididymal luminal environment that supports sperm maturation.