Gene Networks in Peri-pubertal Sertoli Cell Injury

描述(由申请人提供)： 小于胎龄(SGA)出生的儿童在成年后患心血管和代谢性疾病的风险显著增加；然而，关于SGA如何影响性腺发育和生殖健康的数据有限。流行病学研究和登记调查表明，宫内发育异常会使先天性尿道下裂、隐睾症和睾丸癌的风险增加约2-3倍。这些结果的证据表明支持细胞和间质细胞的正常功能发生了变化。动物和人类的研究都表明，青春期周围发育受损会影响睾丸的大小和功能，直到成年。Main等人的一项研究检查了健康的芬兰和丹麦新生儿从出生到3个月大的睾丸发育情况，发现胎龄体重与睾丸大小之间存在显著相关性。因此，阐明调控青春期睾丸生长的信号网络并识别影响这些途径的环境毒物将对环境健康产生重大影响。Akt基因家族影响睾丸发育。AKT1缺陷小鼠出生时胎龄较小，一生中睾丸明显较小。初步数据表明，Akt1信号通路在维持青春期睾丸动态平衡方面起着重要作用。在体内观察到Akt1基因缺陷小鼠暴露于青春期支持细胞毒剂MEHP的生殖细胞凋亡，以及暴露于6-N-丙基硫氧嘧啶(PTU)的小鼠睾丸和生殖能力降低，PTU是一种针对Sertoli细胞增殖和分化的甲状腺毒物。根据这些发现，推测Akt基因家族在青春期周围睾丸发育中起关键作用，在这个发育窗口针对Sertoli细胞的毒物在环境和男性生殖疾病的病因学之间提供了关键的联系。这一假设将通过以下具体目标进行检验：1)明确Akt1抑制MEHP暴露后支持细胞介导的生殖细胞凋亡的机制。2.)确定Akt1在PTU暴露后促进睾丸生长和发育的机制，以及3.确定相关的支持细胞毒物诱导的应激反应网络。相关性：这项研究将定义青春期生殖毒物靶向的关键信号网络，并描述它们如何影响男性生殖健康。

DESCRIPTION (provided by applicant): Children born small for gestational age (SGA) have a significantly elevated risk of cardiovascular and metabolic diseases in adulthood; however, data is limited on how SGA may impact gonadal development and reproductive health. Epidemiological studies and registry surveys demonstrate that altered intrauterine growth increases the risks of congenital hypospadias, cryptorchidism and testicular cancer approximately 2- to 3-fold. Evidence for these outcomes points towards alterations in the normal functions of Sertoli and Leydig cells. Both animal and human studies suggest that impaired peri-pubertal growth can affect testis size and function into adulthood. A study by Main et al., examined testis growth from birth to 3 months of age in healthy Finnish and Danish newborns and found a significant correlation between weight for gestational age and testis size. Therefore, elucidating signaling networks which modulate peri-pubertal testis growth and identifying environmental toxicants which impinge upon these pathways will significantly impact environmental health. The Akt gene family effects testis growth. Akt1 -deficient mice are born small for gestational age and have significantly smaller testis throughout their lifetime. Preliminary data indicate that the Akt1 signaling pathway plays a significant role in maintaining peri-pubertal testicular homeostasis. A striking sensitivity is observed in vivo for germ cell apoptosis in testis of Akt1-deficient mice exposed to MEHP, a peri-pubertal Sertoli cell toxicant, and a reduction in testis and reproductive potential in mice exposed to 6-N-propylthiouracil (PTU), a thyroid toxicant which targets Sertoli cell proliferation and differentiation. Based on these findings, it is hypothesized that the Akt gene family plays a critical role in peri- pubertal testis development and that toxicants which target the Sertoli cell at this developmental window provide a crucial link between the environment and the etiology of male reproductive disease. The hypothesis will be tested through the following Specific Aims: 1.) Identify the mechanisms by which Akt1 suppresses Sertoli cell mediated germ cell apoptosis following MEHP exposure. 2.) Identify the mechanisms by which Akt1 promotes testis growth and development following PTU exposure, and 3.) Identify relevant Sertoli cell toxicant-induced stress response networks. Relevance: This research will define critical signaling networks targeted by peri-pubertal reproductive toxicants and delineate how they impact male reproductive health.