ACTIVATION OF SPERMATOGENIC RECOVERY AFTER TOXIC INSULT

男性暴露在某些环境、职业和医疗环境中 毒物可能导致长时间的少精子症。偶而 精子发生在多年的无精子症后恢复，这表明一些 茎(A型)精原细胞存活，但其分化 有限的。这表明精原细胞分化的中断 可能是导致精子发生无法恢复的原因 在暴露之后。这一假说将在暴露于 生殖毒物对精原细胞分化的调节 荷尔蒙和识别与之相关的分子变化 刺激恢复。辐射和二溴氯丙烷将 作为毒剂使用，因为投放的精确度和 作为环境和职业生殖毒物的相关性， 分别进行了分析。辐射(和DBCP，基于初步数据)产生 在大鼠中，所有分化的生精细胞的丧失，尽管 存在增殖的A精原细胞。失败的原因 精原细胞分化的特征如下。角色 将通过使用单侧激素变化最小化来检查 辐射。激素受体水平降低的可能性 将会被检查。以确定缺陷是在精原细胞还是在精原细胞 将采用基质细胞、细胞移植技术。这个 促性腺激素释放可促进精子发生的恢复 照射后立即给予激素(GnRH)激动剂治疗； 无论这种刺激是由于雄激素水平的改变还是 促性腺激素将会被测定。将进行进一步的研究，以 确定促性腺激素释放激素是否可用于诱导孢子原细胞分化 在发生回归之后。促性腺激素释放激素对生精的刺激作用 恢复，或导致自发性精原细胞的替代模式 从孢子瘤原细胞分化和恢复孢子瘤发生， 将被用来识别调节细胞分化的分子 精原细胞。睾丸中蛋白质或mRNA水平的模式 不分化的孢子原细胞和分化的那些 发生(激素刺激的恢复，替代模式，未经治疗)将 进行比较，以确定其表达与 精原细胞分化。这项研究应该定义不是 不仅调节毒物暴露后孢子母细胞的恢复，而且还 调节正常的孢子原细胞分化。荷尔蒙或其他因素 此项目中确定的可能被用作干预措施，以增强 毒物暴露、癌症治疗后男性生育能力恢复 在一些特发性不孕症的病例中。

Exposure of men to certain environmental, occupational, and medical toxicants may result in prolonged oligoor azoospermia. Occasionally spermatogenesis recovers after years of azoospermia indicating that some stem (type A) spermatogonia survived but their differentiation was limited. This suggests that disruption of spermatogonial differentiation may be responsible for the failure of spermatogenesis to recover following exposure. This hypothesis will be tested in rats exposed to reproductive toxicants by modulating spermatogonial differentiation using hormones and identifying molecular changes associated with the stimulation of recovery. Radiation and dibromochloropropane (DBCP) will be used as the toxicants, because of the precision of delivery and relevance as an environmental and occupational reproductive toxicant, respectively. Radiation (and DBCP, based on preliminary data) produces in rats the loss of all differentiating spermatogenic cells despite the presence of proliferating A spermatogonia. The causes of failure of spermatogonial differentiation will be characterized as follows. The role of hormonal changes will be examined by minimizing them using unilateral irradiation. The possibility that hormone receptor levels are reduced will be examined. To determine whether the defect is in spermatogonia or stromal cells, cell transplantation techniques will be employed. The recovery of spermatogenesis can be stimulated by gonadotropin-releasing hormone (GnRH) agonist treatment given immediately after irradiation; whether the stimulation is a result of altered levels of androgens or gonadotropins will be determined. Further studies will be performed to determine if GnRH can be used to induce spormatogonial differentiation after regression has occurred. GnRH-stimulation of spermatogenic recovery, or alternative models that result in spontaneous spermatogonial differentiation and recovery of spormatogenesis from A spormatogonia, will be used to identify molecules regulating differentiation of spermatogonia. Patterns of protein or mRNA levels in testes in which A spormatogonia do not differentiate and those in which differentiation occurs (hormone-stimulated recovery, alternative models, untreated) will be compared to identify genes whose expression correlates with spermatogonial differentiation. This study should define factors that not only modulate spormatogenic recovery after toxicant exposure but also regulate normal spormatogonial differentiation. Hormones or other factors identified in this project might be used as intervention to enhance recovery of fertility in men following toxicant exposure, cancer therapy, and in some cases of idiopathic infertility.