EXAMINATION OF STRESS RESPONSE GENES FOLLOWING MEHP-INDUCED TESTICULAR INJURY

MEHP 引起的睾丸损伤后应激反应基因的检查

• 批准号: 7381999
• 负责人: MARY L HIXON
• 金额: $ 1.13万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381999
• 关键词: EXAMINATION; STRESS; RESPONSE; GENES; FOLLOWING

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。邻苯二甲酸盐是一组化学物质，可赋予塑料其锻造性。人类接触邻苯二甲酸盐是无处不在的。特别关心的是，胎儿，早产儿和婴儿暴露于生物医学设备导致的暴露和摄入受污染的食物中的暴露。在啮齿动物模型中，邻苯二甲酸酯的暴露会导致多种生殖异常，包括睾丸激素合成降低，静脉距离降低，隐齿术，不育和异常的生精管形成。 DI（2-乙基己基）邻苯二甲酸酯（DEHP）已被证明会损害新生动物中的雄性和女性生殖系统。 MEHP是增塑剂，DEHP和已知睾丸细胞有毒物质的活性代谢物。尽管进行了许多研究，但缺乏控制邻苯二甲酸酯损伤的分子旁小鼠模型和分子途径。该试验项目的目的是鉴定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传导途径涉及的基因。我们的初步数据表明，在体内暴露于MEHP的Akt1缺陷小鼠的睾丸中，对生殖细胞凋亡的敏感性显着，这既表明Akt1在Per otubertal生殖细胞的存活中既有至关重要的作用，又表明了该小鼠用作螺旋伯伯质损伤模型的使用。利用基因组微阵列技术，我们将首先检查Akt1野生型睾丸基因表达和暴露于MEHP的Akt1缺陷小鼠，以鉴定参与AKT1介导的细胞存活途径的基因。其次，我们将确定p53是否与对MEHP诱导的睾丸损伤的抗性有关的基因是否通过检查MEHP暴露后AKT1/p53双缺陷小鼠中的睾丸基因表达来调节Akt1介导的反应。 相关性：新基因的鉴定将导致临床生物标志物的发展，这将鉴定出暴露于邻苯二甲酸盐毒性水平的新生儿。该研究的最终目的是确定可以在临床环境中操纵的发育途径，以最大程度地减少或防止邻苯二甲酸酯的毒性暴露。