Mechanisms of phthalate-induced ovarian follicle toxicity

描述(由申请人提供) 这项申请的目的是为了支持伊利诺伊大学比较生物科学系博士后泽利安·R·克雷格博士过渡到独立的研究生涯。克雷格博士将接受乔迪·A·弗洛斯博士的指导。这项申请的主要目标是为克雷格·威尔博士提供所有必要的技术和专业技能，使她成为一名成功的独立调查员和她所在领域的领导者。在这项提案的研究培训部分，克雷格博士将研究邻苯二甲酸盐--一组内分泌干扰物--导致卵泡毒性的机制。此外，她将研究主要的卵巢雌激素17-β-雌二醇部分阻止邻苯二甲酸盐对卵巢卵泡影响的机制。特定目的1将确定邻苯二甲酸盐是否通过减少卵泡细胞的增殖来抑制小鼠卵巢卵泡的生长。特定目的2将确定邻苯二甲酸盐是否通过诱导卵泡细胞凋亡来抑制小鼠卵巢卵泡的生长。最后，具体目标3将 确定17-β-雌二醇阻止邻苯二甲酸盐抑制小鼠卵巢卵泡生长和增加卵泡死亡的机制。这些研究的结果将提供关于邻苯二甲酸酯的生殖毒性以及这些化学品的作用机制的基本信息。因此，这些研究的结果可能有助于旨在发现治疗环境化学物质暴露引起的不孕不育的潜在靶点的研究。 公共卫生相关性：这个项目将帮助Zelieann Craig博士成功地成长为一名独立研究员。通过这里提出的实验，克雷格博士将有助于扩大我们对邻苯二甲酸盐影响卵巢功能并导致动物模型不孕的机制的了解。最后，该项目的结果还将有助于研究旨在确定新的治疗方法，以扭转环境化学物质暴露造成的女性不孕。

DESCRIPTION (provided by applicant) The purpose of this application is to support the transition of Dr. Zelieann R. Craig, a postdoctoral fellow in the Department of Comparative Biosciences at the University of Illinois, into an independent research career. Dr. Craig will be mentored by Dr. Jodi A. Flaws. The main goal of this application is to provide Dr. Craig will all the technical and professional skills necessary for her to become a successful independent investigator and leader in her field. In the research training component of this proposal, Dr. Craig will investigate the mechanisms by which phthalates, a group of endocrine disrupting chemicals, cause ovarian follicle toxicity. Further, she will investigate the mechanism by which 17-beta-estradiol, the major ovarian estrogen, partially prevents the effects of phthalates on ovarian follicles. Specific aim 1 will determine whether phthalates suppress growth of mouse ovarian follicles by decreasing proliferation of follicular cells. Specific aim 2 will determine whether phthalates suppress growt of mouse ovarian follicles by inducing apoptosis in follicular cells. Finally, specific aim 3 will determine the mechanism by which 17-beta-estradiol prevents phthalate-induced suppression of mouse ovarian follicle growth and increased follicular death. Findings from these studies will provide basic information on the reproductive toxicity of phthalates as well as mechanisms of action for these chemicals. Thus, findings from these studies may contribute to research aimed at the discovery of potential targets for the treatment of infertility caused by environmental chemical exposure. Public Health Relevance: This project will help Dr. Zelieann Craig successfully mature into an independent researcher. Through the experiments proposed here, Dr. Craig will contribute to expanding our knowledge on the mechanisms by which phthalates affect ovarian function and cause infertility in animal models. Finally, results from this project will also contribute to research aimed at the identification of new treatments to reverse female infertility caused by environmental chemical exposure.