EXAMINATION OF STRESS RESPONSE GENES FOLLOWING MEHP-INDUCED TESTICULAR INJURY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 邻苯二甲酸酯是一组化学物质，使塑料具有延展性。人类接触邻苯二甲酸盐是普遍存在的。特别值得关注的是胎儿、早产儿和婴儿因生物医学器械和摄入受污染食物而暴露于邻苯二甲酸酯。在啮齿动物模型中，邻苯二甲酸酯暴露导致各种生殖异常，包括睾酮合成减少、肛门生殖器距离缩短、隐睾、不育和异常生精小管形成。邻苯二甲酸二（2-乙基己基）酯（DEHP）已被证明会损害新生动物的雄性和雌性生殖系统。MEHP是增塑剂DEHP的活性代谢产物，也是一种已知的睾丸细胞毒物。尽管有许多研究，但缺乏青春期小鼠模型和控制邻苯二甲酸酯损伤的分子途径。该试点项目的目标是确定参与邻苯二甲酸酯暴露后介导睾丸细胞死亡的分子和细胞信号通路的基因。我们的初步数据表明，在体内暴露于MEHP的Akt 1缺陷小鼠的睾丸中，对生殖细胞凋亡具有惊人的敏感性，这表明Akt 1在青春期周围生殖细胞的存活中起着关键作用，并将该小鼠用作青春期周围暴露于邻苯二甲酸酯损伤的模型。利用基因组微阵列技术，我们将首先检查睾丸基因表达的Akt 1野生型和Akt 1缺陷型小鼠暴露于MEHP，以确定参与Akt 1介导的细胞存活途径的基因。其次，我们将确定是否p53，一个基因参与抵抗MEHP诱导的睾丸损伤，调节Akt 1介导的反应，检查睾丸基因表达的Akt 1/p53双缺陷小鼠后MEHP曝光。 相关性：新基因的鉴定将导致临床生物标志物的开发，这些生物标志物将识别暴露于邻苯二甲酸酯毒性水平的新生儿。该研究的最终目标是确定可在临床环境中操作的发育途径，以最大限度地减少或防止邻苯二甲酸酯的毒性暴露。

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. Phthalates are a group of chemicals which give plastics their malleability. Human exposure to phthalates is ubiquitious. Of particular medical concern, is the exposure of fetuses, preterm infants, and babies to phthalates from exposures resulting from biomedical devices and through ingestion of contaminated foods. In rodent models, phthalate exposure leads to a variety of reproductive abnormalities including decreased testosterone synthesis, reduced anogenital distance, cryptorchidism, infertility, and aberrant seminiferous tubule formation. Di (2-ethylhexyl) phthalate (DEHP) has been shown to damage male and female reproductive systems in newborn animals. MEHP is the active metabolite of the plasticizer, DEHP, and a known testicular cell toxicant. In spite of numerous studies, peri-pubertal mouse models and the molecular pathways which control phthalate injury are lacking. The goal of this pilot project is to identify genes involved in the molecular and cellular signaling pathways which mediate testicular cell death following phthalate exposure. Our preliminary data indicate a striking sensitivity to germ cell apoptosis in the testes of Akt1-deficient mice exposed to MEHP in vivo, demonstrating both a critical role for Akt1 in the survival of peri-pubertal germ cells and use of this mouse as a model for peri-pubertal exposure to phthalate injury. Utilizing genomic microarray technologies, we will first examine testis gene expression in Akt1 wild type and Akt1 deficient mice exposed to MEHP to identify genes involved in an Akt1-mediated cell survival pathway. Second, we will determine if p53, a gene implicated in resistance to MEHP-induced testis injury, modulates the Akt1-mediated response by examination of testis gene expression in Akt1/p53 double deficient mice following MEHP exposure. Relevance: The identification of novel genes will lead to the development of clinical biomarkers which will identify neonates exposed to toxic levels of phthalates. The ultimate goal of the research is to identify developmental pathways which can be manipulated in a clinical setting to minimize or prevent toxic exposure to phthalates.