Molecular Mechanism of Human Fetal Testis Susceptibility to Endocrine Disruption

描述（由申请方提供）：“睾丸发育不全综合征”被提出来解释在过去的半个世纪中报告的人类男性生殖道异常患病率的增加。根据这一假说，所观察到的异常，包括畸形外生殖器（尿道下裂），隐睾（隐睾），生精缺陷，睾丸生殖细胞癌，结果在子宫内和围产期激素环境的改变引起敏感的男性生殖道发育事件中断。人们的注意力集中在环境内分泌干扰化学品作为这种发育中断的可能原因。 邻苯二甲酸酯是普遍存在的环境污染物和内分泌干扰物。在雄性生殖道发育的关键宫内窗口期暴露于邻苯二甲酸二丁酯（DBP）的大鼠，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全综合征相关的生殖道异常。令人惊讶的是，在我们实验室进行的最近的工作中，我们发现，与大鼠不同，胎鼠睾丸对DBP的睾酮和类固醇生成酶抑制作用具有抗性。睾丸发育不全反应的种属特异性的观察提出了两个重要的问题，本申请解决：什么是内分泌活性毒物对胎儿睾丸类固醇生成的影响的分子途径决定因素？人类胎儿睾丸对包括DBP在内的内分泌干扰物的反应是什么？ 在该项目中，考虑到宿主激素状态、暴露参数和固有睾丸对宿主的易感性，对移植到啮齿动物宿主中的胎儿睾丸的异种移植物生物测定进行了优化。然后确定大鼠、小鼠和人胎睾丸异种移植物对模型内分泌活性毒物（己烯雌酚[DES]和DBP）的剂量反应。使用分子分析，基因分析和建模，胎儿睾丸对这些内分泌干扰物的反应的比较生物学将被探索，确定易感性的生物标志物。这些目标将追求以下工作假设作为指导：暴露的异种移植生物测定预测人胎儿睾丸内分泌活性毒物的敏感性。 公共卫生相关性：人类男性生殖道异常（精子计数下降、尿道下裂、隐睾症和睾丸生殖细胞癌）的增加被归咎于改变子宫内和围产期激素环境的环境暴露。该项目将开发一种异种移植物生物测定法，包括将胎儿睾丸植入啮齿动物宿主，以直接评估人类对内分泌干扰化学品（包括增塑剂邻苯二甲酸二丁酯）的敏感性。

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. PUBLIC HEALTH RELEVANCE: Increases in human male reproductive tract abnormalities (falling sperm counts, hypospadias, cryptorchidism, and testis germ cell cancer) have been blamed on environmental exposures that alter the in utero and perinatal hormonal milieu. This project will develop a xenograft bioassay consisting of fetal testes implanted in a rodent host to directly assess human susceptibility to endocrine disrupting chemicals, including the plasticizer di-n-butyl phthalate.