Genetic defects or toxicant exposure often result in blocks in early germ cell development, but in some cases elevation of temperature or lowering testosterone levels can overcome this block. This suggests that the low scrotal temperatures and high intratesticular testosterone may not be optimal for spermatogonial and spermatocyte development in these pathological cases, and that effects restorative of testosterone suppression and elevated temperature might be mechanistically linked. We hypothesize that suppression of testosterone elevates testicular temperature, which then enhances general or specific metabolic events to overcome genetic or toxicant induced blocks. The juvenile spermatogonial depletion (jsd) mutant mouse is one model to study the mechanisms by which elevated temperature and hormone suppression can alleviate the block in spermatogonial differentiation. Jsd is a mutation in the Utp14b gene, which is involved in ribosomal RNA processing. Utp14b is a copy of the widely expressed (except spermatocytes) X linked Utp14a gene. Utp14b is mainly expressed in germ cells. We propose that in jsd mice, testosterone suppression leads to a gradual temperature increase, which restores ribosomal RNA processing by upregulating Utp14a in spermatogonia and/or spermatocytes. We will test between this model and alternatives with the following Specific Aims: (I) Determine whether testosterone suppression elevates testicular temperature in vivo, whether testosterone inhibits spermatogonial differentiation by acting on cells involved in temperature regulation, and whether temperature but not testosterone affects differentiation in vitro. (II) Determine if 18S ribosomal RNA processing is defective in both spermatogonia and spermatocytes of jsd mice at scrotal temperatures, and if processing is more efficient at body temperature. (III) Determine the specific or general metabolic processes that are altered by elevation of temperature to overcome the defects in germ cell differentiation. If temperature elevation restores 18S rRNA processing in jsd mice, then increases in Utp14a levels in germ cells will be examined as a specific compensatory mechanism. In addition, (IV) we will evaluate the application of testosterone suppression and elevated temperature to enhance spermatogonial development in irradiated mice, a toxicant induced model of hypospermatogenesis. These results will provide insight into the molecular mechanisms underlying aspects of temperature and androgen effects on spermatogenesis and reveal a direct mechanistic link between these two modulators. This information would significantly contribute to both our basic understanding of the biological mechanisms involved in spermatogenesis, and to possible treatments for oligospermia or azoospermia in men. ? ? Partial or complete blocks at the early stages of spermatogenesis results in low or zero sperm counts, a problem that appears to be increasing in men. Elucidation of the causes of such blocks and the mechanisms by which temperature elevation and hormone suppression can reverse them in experimental animal models could apply to treatment of genetically or environmentally caused male infertility in humans. Further, proof of our hypothesis that the effects of testosterone suppression and temperature elevation are mechanistically linked would lead to new insights and interpretations of published research. ? ? ?
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