GROWTH CONTROL IN THE TESTIS AND MOLECULAR MECHANISMS OF TESTICULAR HOMEOSTASIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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如何影响生殖发育的数据有限。研究表明，宫内发育异常会增加先天性尿道下裂、隐睾症和睾丸癌的风险，大约是前者的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都发生了变化。动物和人类的研究表明，青春期周围发育受损会影响睾丸的大小和功能，直到成年。因此，阐明调控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。我们的实验室专注于Akt1信号通路及其在维持青春期睾丸动态平衡中的作用。我们发现，在Akt1基因缺陷小鼠中，暴露于青春期支持细胞毒剂邻苯二甲酸单乙基己酯(MEHP)的睾丸对生殖细胞凋亡具有显著的敏感性；暴露于6-N-丙基硫氧嘧啶(PTU)的小鼠的睾丸大小和生殖潜力减少，PTU是一种针对支持细胞增殖和分化的甲状腺毒物。基于这些发现，我们假设Akt基因家族在青春期睾丸动态平衡中起关键作用，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。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 reproductive development. Studies indicate that altered intrauterine growth increases the risk of congenital hypospadias, cryptorchidism, and testicular cancer approximately 2- to 3- fold. Evidence for these outcomes points towards alterations in the normal function of both the Sertoli and Leydig cells. Animal and human studies suggest that impaired peri-pubertal growth can affect testis size and function into adulthood. Therefore, elucidating signaling networks which modulate testis growth and identifying environmental toxicants which impinge upon these pathways will significantly impact environmental health. Our lab focuses on the Akt1 signaling pathway and its role in maintaining peri-pubertal testicular homeostasis. We have found a striking sensitivity to germ cell apoptosis in vivo in the testis of Akt1-deficient mice exposed to mono-2- ethylhexyl-phthalate (MEHP), a peri-pubertal Sertoli cell toxicant; and a reduction in testis size 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, we hypothesize that the Akt gene family plays a critical role in peri-pubertal testis homeostasis 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.