Impact of Endocrine Disrupter on Primate Spermatogenesis

描述(由申请人提供) 这项提案的长期目标是通过以下方式系统地审查 结合生理、细胞和分子方法，直接 内分泌干扰物(ED)对青春期睾丸发育的影响 非人灵长类动物模型。目前的想法是，EDS可能解释了 男性生殖障碍在男孩中的发展和显著下降 据报道，在过去的几十年里，男性的精子数量发生了变化。 到目前为止，这些重要的问题都是通过使用 啮齿动物模型，这可能不是最适合人类的范例 繁殖。本提案将首次涉及这一问题 使用非人类灵长类动物模型的问题。首席调查员将 确定辛基酚对幼猴的治疗是否会产生 对睾丸的直接影响导致a)支持细胞数量的减少 细胞，b)间质细胞产生的睾酮减少，c)减少 干细胞(A暗细胞和A苍白细胞)的数量，以及d)在 内分泌/旁分泌相互作用相关基因的表达和功能 在脑下垂体-睾丸轴上。青春期前灵长类动物“睾丸夹” 将制备的睾丸作为实验模型，并与性早熟进行比较 通过刺激未成熟猴子的睾丸来诱导青春期 生理方式不变间歇输注外源激素 重组猴促性腺激素(卵泡刺激素和黄体生成素)和辛基酚(2 ng/g体重 体重)将每天给药。猴子将被阉割，而 辛基酚对支持细胞、间质细胞和干细胞数量的影响 对内分泌/旁分泌相关基因表达的影响 睾丸中的相互作用。这项研究的结果将确定 青春期辛基酚对睾丸影响的潜在部位。 此外，本研究还将建立青春期前灵长类动物的睾丸 夹具制备作为常规检查的上佳模型 精神分裂症对人类的影响。

DESCRIPTION (provided by applicant) The long-term objective of this proposal is to systematically examine, by integrating physiological, cellular and molecular approaches, the direct effects of endocrine disruptors (ED) on pubertal testicular development using a non-human primate model. Current thinking is that EDs may account for the development of male reproductive disorders in boys and a significant decline in sperm count in men reported to have occurred during the past few decades. To date, these important issues have been experimentally evaluated using rodent models, which may not serve as a most appropriate paradigm for human reproduction. The present proposal will address, for the first time, this issue using a non-human primate model. The principal investigator will determine whether treatment with Octylphenol in juvenile monkeys would exert direct effects on the testis leading to a) decrease in the number of Sertoli cells, b) decrease in testosterone production by Leydig cells, c) decrease in the number of stem (A-dark and A-pale) cells, and d) alterations in the expression and function of genes involved in endocrine/paracrine interactions in the pituitary testicular axis. A prepubertal primate "testicular clamp" preparation will be used as an experimental model, and precocious testicular puberty will be induced by stimulating the testes of immature monkey in a physiological manner with invariant intermittent infusion of exogenous recombinant monkey gonadotropins (FSH and LH) and Octylphenol (2 ng/g body weight) will be administered daily. The monkeys will be castrated and the impact of Octylphenol on Sertoli cell, Leydig cell, and stem cell numbers will be determined and on the expression of genes involved in endocrine/paracrine interaction in the testis. The results from this study will identify potential sites of testicular effects of Octylphenol during puberty. Moreover, this study will also establish the prepubertal primate testicular clamp preparation as a superior model for the general examination of the effects of EDs in man.