Activation of Spermatogenic Recovery After Toxic Insult

中毒后生精恢复的激活

• 批准号: 7847973
• 负责人: Marvin L. Meistrich
• 金额: $ 1.54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847973
• 关键词: Affect; Biological Models; Cell Transplants; Chemicals; Code; Defect; Development; Differentiation and Growth; Edema; Elements; Environment; Estradiol; Exposure to; Genes; Goals; Growth Factor; Hereditary Disease; Histologic; Hormonal; Hormones; In Vitro; Intercellular Fluid; KITLG gene; Laboratories; Liquid substance; Male Infertility; Mediating; Methods; Microarray Analysis; Modeling; Molecular; Monkeys; Pattern; Procedures; Proteins; Radiation; Rattus; Recovery; Regulation; Research Personnel; Rodent; Role; Seminiferous tubule structure; Somatic Cell; Source; Sperm Count Procedure; Spermatogenesis; Spermatogonia; Stem cells; System; Testicular Tissue; Testing; Testis; Testosterone; Toxicant exposure; Transplantation; cell injury; chemical group; environmental agent; improved; in vivo; interstitial; interstitial cell; irradiation; leydig interstitial cell; macrophage; macrophage product; man; men; molecular marker; paracrine; preclinical study; prepuberty; programs; protein expression; receptor; reproductive; sertoli cell; sperm cell; stem; steroid hormone; toxicant

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.

项目简介：本研究旨在阐明大鼠接触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，并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其与化学毒物的相关性。特别是，将研究辐射通过破坏体细胞环境而不是破坏精原细胞而引起精原细胞分化阻滞的结论是否适用于DBCP。在辐照大鼠中，确定受睾酮调节影响精原细胞分化的因素来源和具体因素。以往的结果表明，存在或通过间质传递的因素是重要的。这一假设将通过检测睾丸体细胞或小管移植后或产生旁分泌因子的间质间质细胞或巨噬细胞选择性耗竭后的体内精原细胞分化，以及评估间质液对体外精原细胞分化的影响来验证。下一步，将进一步测试受睾酮和卵泡刺激素调节的与精原细胞分化协调的生长和分化因子编码基因与其他激素调节的精原细胞分化的相关性；最相关的基因将与它们的受体一起深入研究。体外系统将用于确定睾酮或其他激素是否独立于体内发生的系统效应直接调节精原细胞分化，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，在这个模型中，辐射和化学毒物会使啮齿动物的精子长期减少或缺失，尽管存在精原干细胞。我们还开发了激素方法来逆转精子发生中的这种阻滞；然而，地磁块及其反转的机制尚不清楚。必须阐明这些机制，以便确定如何将扭转这种障碍的方法应用于人类。