Activation of Spermatogenic Recovery After Toxic Insult

描述(申请人提供)：项目摘要：本研究的目的是阐明睾丸激素抑制毒物暴露后大鼠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，并将通过与二溴氯丙烷(DBCP)暴露后的结果相比较来评估与化学毒物的相关性。特别是，将研究辐射通过破坏躯体环境而不是精原细胞而导致精原细胞分化障碍这一结论在DBCP中的推广。在照射的大鼠中，将确定影响精原细胞分化的因素的来源和受睾酮调节的特定因素。先前的结果表明，存在或通过间质传递的因子是重要的。这一假设将在睾丸体细胞或小管移植后，或在选择性地耗尽产生旁分泌因子的间质细胞或巨噬细胞后，通过检测体内精原细胞的分化，以及通过评估间质液体对体外精原细胞分化的影响来验证。接下来，由睾酮和FSH以与精原细胞分化相协调的方式调节生长和分化因子的基因将进一步测试它们与精原细胞分化的相关性，使用其他激素调节；最相关的基因将与其受体一起进行深入研究。体外系统将被用来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，还将测试由睾酮调节的特定蛋白质因素是否影响精原细胞分化。相关性：越来越多的男性精子数低，可能是由于暴露在已知和未知的环境因素中。我们已经开发出一种模型，在该模型中，尽管存在精原干细胞，辐射和化学毒物在啮齿类动物中仍会导致精子长期减少或缺失。我们还开发了荷尔蒙方法来逆转精子发生中的这一阻断；然而，阻断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一障碍的方法应用于人类。

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.