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.
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