Phthalates and Ovarian Toxicity

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 DESCRIPTION (provided by applicant): Female fertility depends on the development of an adequate number of healthy primordial ovarian follicles as well the constant growth of primordial follicles to primary follicles then to pre-antral follicles and eventually to antral follicles, whih are the only follicles capable of releasing an egg for fertilization and synthesizing sex steroid hormones. Because a finite ovarian reserve is established at birth and follicular growth (folliculogenesis) is an irreversible process, aberrant regulation of folliculogenesis can have adverse reproductive implications. In particular, accelerated depletion of primordial follicles, particularly through irregular activation of primordial follicles to primary follicles, can result n infertility and premature ovarian failure. Despite the importance of folliculogenesis for fertility and health, we know very little about the environmental factors that control the growth of follicle from the primordial to primary stage. Our preliminary data indicate that the endocrine disrupting chemical di(2-ethylhexyl) phthalate (DEHP) and one of its primary metabolites mono(2-ethylhexyl) phthalate (MEHP) accelerate folliculogenesis in mice. Further, our preliminary data indicate that DEHP dysregulates the levels of key components of a pathway that regulates folliculogenesis, the phosphoinositide 3-kinase (PI3K) signaling pathway. These data are of concern because phthalates have been identified as one of the top contaminants present in human tissues and they are present in a myriad of consumer products, personal care products, pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and medical devices. Given our preliminary data, the importance of normal fertility for reproductive and non-reproductive health, and the ubiquitous exposure of humans to phthalates, we propose to use mice to test the hypothesis that exposure to phthalates and their metabolites accelerates ovarian folliculogenesis through the PI3K pathway, leading to infertility and premature ovarian failure. To test this hypothesis, we propose the following three specific aims: 1) determine if environmentally relevant doses of phthalates (DEHP, MEHP, and a phthalate mixture) accelerate ovarian folliculogenesis via the PI3K pathway, 2) determine if the ovary has the capacity to respond to phthalate metabolites and to metabolize DEHP and the phthalate mixture into toxic metabolites, and 3) determine if phthalate-induced acceleration of folliculogenesis leads to infertility and premature ovarian failure. Collectively, the proposed work will determine the mechanisms by which phthalates cause ovarian toxicity and reproductive dysfunction in female mammals and in turn, this may lead to the development of novel targets for the treatment of phthalate-induced diseases.