While controversial, reports of a dramatic decrease in human sperm counts due to exposure to environmental toxicants are alarming. All agree that infertility is common, affecting one out of every eight couples, and that male dysfunction accounts for half of this incidence. """"""""Irreversible"""""""" testicular injury is a form of male infertility in which proliferating germ cells fail to repopulate the testis because they die prematurely by programmed cell death (apoptosis). 2,5-Hexanedione is an environmental toxicant that produces irreversible testicular injury in the rat. After a decade of investigation, this rat model is sufficiently well characterized to study the underlying mechanisms of testicular failure in irreversible injury. Two recent discoveries have primed this research area for a major advance. First, the apoptosis-inducing Fas system, with Sertoli cells expressing Fas ligand and germ cells expressing Fas receptor, has been identified as a key regulator of germ cell survival. This new appreciation for the role of apoptosis in modulating germ cell homeostasis, when combined with the known importance of growth factors like stern cell factor, leads to the following working hypothesis: the failure of germ cell survival in toxicant-induced irreversible testicular injury is explained by a disruption in the balance between growth factor support and death-inducing factors in the local paracrine environment. Second, irreversible injury can be rescued by lowering the intratesticular testosterone concentration with leuprolide.
Three Specific Aims are designed to exploit this new information as follows: 1) using the Fas ligand deficient gld mutant mouse and p53 knockout mouse, identify the signal and execution elements which modulate germ cell apoptosis, 2) follow the expression of growth and death factors during leuprolide- induced rescue, and 3) test specific targets of irreversible injury by delivering adenovirus expressing transmembrane stem cell factor and by infusing caspase inhibitors with Alzet minipumps. Together, these complimentary approaches will elucidate the key molecular mechanisms responsible for irreversible testicular injury.
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