Activation of Spermatogenic Recovery After Toxic Insult

描述（由申请人提供）：项目总结：本研究的目的是阐明大鼠暴露于毒物后睾酮抑制精原细胞分化的机制。在大多数研究中，辐射将被用作模型毒物，与化学毒物的相关性将通过与二溴氯丙烷（DBCP）暴露后获得的结果进行比较来评估。特别是，延伸到DBCP的结论，辐射诱导精原细胞分化阻滞通过破坏体细胞环境，而不是精原细胞，将进行检查。在受照射的大鼠中，这些因素的来源以及受睾酮调节以影响精原细胞分化的特定因素将被确定。以前的结果表明，通过氚存在或传播的因素是重要的。这一假设将通过检查睾丸体细胞或小管移植后或选择性耗竭间质间质细胞或巨噬细胞（产生旁分泌因子）后体内精原细胞分化，以及通过评估间质液对体外精原细胞分化的影响来检验。接下来，将进一步检测由睾酮和FSH以与精原细胞分化协调的方式调节的生长和分化因子的编码基因，以确定其与使用其他激素调节的精原细胞分化的相关性;将深入研究最相关的基因，沿着其受体。体外系统将用于确定睾酮或其他激素是否直接调节精原细胞分化，而不依赖于体内发生的全身效应，并测试睾酮调节的特定蛋白质因子是否影响精原细胞分化。相关性：越来越多的男性精子数量低，可能是由于暴露于已知和未知的环境因素。我们已经开发了一个模型，其中辐射和化学毒物产生长期减少或没有精子在啮齿动物，尽管存在精原干细胞。我们还开发了逆转精子发生中这种阻滞的激素方法;然而，这种阻滞及其逆转的机制尚不清楚。必须阐明这些机制，以确定如何将逆转这种阻滞的方法应用于人类。

DESCRIPTION (provided by applicant): Project Summary: The objective of this study is to elucidate the mechanism by which testosterone inhibits spermatogonial differentiation after toxicant exposure of rats. Radiation will be used as a model toxicant in most studies and the relevance to chemical toxicants will be assessed by comparison with results obtained after dibromochloropropane (DBCP) exposure. In particular, the extension to DBCP of the conclusion that radiation induces the spermatogonial differentiation block by damaging the somatic environment, not the spermatogonia, will be examined. In irradiated rats, the source of the factors and the specific factors that are regulated by testosterone to affect spermatogonial differentiation will be identified. Previous results indicated that factors present or transmitted through the interstitium are important. That hypothesis will be tested by examining spermatogonial differentiation in vivo after testicular somatic cell or tubule transplantations or after selective depletion of the interstitial Leydig cells or macrophages, which produce paracrine factors, and by assessing the effects of interstitial fluid on spermatogonial differentiation in vitro. Next, genes coding for growth and differentiation factors that are regulated by testosterone and FSH in a manner coordinate with spermatogonial differentiation will be further tested for their correlation with spermatogonial differentiation using other hormonal modulations; the gene that best correlate will be studied, along with their receptors, in depth. An in vitro system will be used to determine whether testosterone or other hormones directly modulate spermatogonial differentiation independent of systemic effects that occur in vivo and also to test whether the specific protein factors regulated by testosterone affect spermatogonial differentiation. Relevance: An increasing number of men have low sperm counts, possibly due to exposure to known and unknown environmental agents. We have developed a model in which radiation and chemical toxicants produce prolonged reduction or absence of sperm in rodents, despite the presence of spermatogonial stem cells. We have also developed hormonal methods for the reversal of this block in spermatogenesis; however the mechanisms of the block and its reversal are unknown. It is essential to elucidate these mechanisms in order to determine how methods for reversal of that block could be applied to man.