ACTIVATION OF SPERMATOGENIC RECOVERY AFTER TOXIC INSULT

男性暴露于某些环境、职业和医疗条件， 毒物可能导致长期少精或无精。偶尔 精子发生在多年无精子症后恢复，这表明一些 A型精原细胞存活，但其分化受到抑制。 有限公司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 暴露后。这一假设将在暴露于 生殖毒物通过调节精原细胞分化 激素和识别与 刺激复苏。辐射和二溴氯丙烷（DBCP）将 由于输送的精确性， 作为环境和职业生殖毒物的相关性， 分别辐射（和二溴氯丙烷，根据初步数据）产生 在大鼠中，尽管有 A型精原细胞增殖。失败的原因 精原细胞分化的特征如下。的作用 将通过使用单侧 辐照 激素受体水平降低的可能性 将被审查。以确定缺陷是否在精原细胞或 基质细胞，将采用细胞移植技术。的 促性腺激素释放可以刺激精子发生的恢复 照射后立即给予激素（GnRH）激动剂治疗; 刺激是否是雄激素水平改变的结果， 将测定促性腺激素。将进行进一步研究， 确定GnRH是否可用于诱导孢子生殖分化 回归之后。促性腺激素释放激素刺激生精 恢复，或导致自发精原细胞 从孢子原细胞中分化和恢复孢子发生， 将用于鉴定调节分化的分子， 精原细胞睾丸中蛋白质或mRNA水平的模式， 孢子原细胞不分化， 发生（药物刺激恢复，替代模型，未治疗）将 进行比较，以确定其表达与以下相关的基因： 精原细胞分化这项研究应确定不 不仅调节毒物暴露后的孢子发生恢复， 调节正常的孢子生殖分化。激素或其他因素 本项目中确定的可用作干预措施， 在毒物暴露、癌症治疗、 以及一些特发性不孕症。

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.