Molecular Mechanism of Human Fetal Testis Susceptibility to Endocrine Disruption

描述（由申请人提供）：“睾丸发育不良综合征”已被提出来解释在过去的半个世纪中人类男性生殖道异常患病率的增加。根据这一假说，观察到的异常——包括外生殖器畸形（尿道下裂）、睾丸隐睾、生精缺陷和睾丸生殖细胞癌——是由于子宫内和围产期激素环境的改变，导致敏感的男性生殖道发育事件中断。人们把注意力集中在环境内分泌干扰化学品上，认为它们可能是造成这种发育中断的原因。邻苯二甲酸盐是普遍存在的环境污染物和内分泌干扰化学物质。在雄性生殖道发育的关键子宫窗期，大鼠暴露于邻苯二甲酸二丁酯（DBP）会导致胎儿睾丸睾酮分泌减少，基因表达改变（包括类固醇基因表达减少），以及许多与睾丸发育不良综合征相关的生殖道异常。令人惊讶的是，在我们实验室最近进行的工作中，我们发现，与大鼠不同，胎鼠的睾丸对DBP的睾酮和甾体原酶抑制作用具有抗性。这种对睾丸发育不良反应的物种特异性的观察提出了本应用程序解决的两个重要问题：内分泌活性毒物对胎儿睾丸类固醇形成影响的分子途径决定因素是什么？人类胎儿睾丸对包括DBP在内的内分泌干扰物有何反应？在这个项目中，考虑到宿主的激素状态、暴露参数和固有的睾丸对宿主的敏感性，对移植到啮齿动物宿主中的胎儿睾丸的异种移植生物测定进行了优化。然后将确定大鼠、小鼠和人胎儿睾丸异种移植对内分泌活性毒物（己烯雌酚[DES]和DBP）的剂量反应。利用分子分析、基因谱分析和建模，将探索胎儿睾丸对这些内分泌干扰物反应的比较生物学，确定易感性的生物标志物。这些目标将以以下工作假设为指导：暴露于异种移植生物测定预测人类胎儿睾丸对内分泌活性毒物的易感性。

DESCRIPTION (provided by applicant): "Testicular Dysgenesis Syndrome" has been proposed to explain the reported increase in the prevalence of human male reproductive tract abnormalities during the past half century. According to this hypothesis, the observed abnormalities-including malformed external genitalia (hypospadias), undescended testis (cryptorchidism), spermatogenic defects, and testis germ cell cancer-result from alterations in the in utero and perinatal hormonal milieu causing disruption of sensitive male reproductive tract developmental events. Attention has focused on environmental endocrine disrupting chemicals as possible causes of this developmental disruption. Phthalates are ubiquitous environmental contaminants and endocrine disrupting chemicals. Rats exposed to di-(n-butyl)phthalate) (DBP) during a critical in utero window of male reproductive tract development have decreased fetal testicular testosterone secretion, altered gene expression (including decreased steroidogenic gene expression), and many of the reproductive tract abnormalities associated with testicular dysgenesis syndrome. Surprisingly, in recent work conducted in our laboratories, we have discovered that, unlike the rat, fetal mouse testes are resistant to the testosterone and steroidogenic enzyme inhibitory effects of DBP. This observation of species specificity in the testicular dysgenesis response raises two important questions addressed by this application: What are the molecular pathway determinants of an effect of endocrine active toxicants on fetal testicular steroidogenesis? And what is the human fetal testicular response to endocrine disrupting chemicals, including DBP? In this project, a xenograft bioassay of fetal testes transplanted into a rodent host is optimized, considering host hormonal status, exposure parameters, and intrinsic testicular versus host susceptibility. The dose response of rat, mouse, and human fetal testis xenografts to model endocrine active toxicants (diethylstilbestrol [DES] and DBP) will then be determined. Using molecular analyses, gene profiling, and modeling, the comparative biology of the fetal testicular response to these endocrine disruptors will be explored, identifying biomarkers of susceptibility. These goals will be pursued with the following working hypothesis as a guide: Exposure of a xenotransplant bioassay predicts human fetal testicular susceptibility to endocrine active toxicants.