Impact of Epidemiologically Based Phthalate Exposures on Female Reproduction and Metabolism

PROJECT SUMMARY/ABSTRACT Phthalates are used in beauty and personal care products, food packaging, medical devices, and the coating of some medications. Human biomonitoring analyses demonstrate constant human phthalate exposure due to the ability of these chemicals to leach from these products. Many epidemiological studies have reported associations between phthalate burden and human metabolic and reproductive health outcomes. Women of reproductive age are considered a high exposure/high risk population based on biomonitoring data showing higher phthalate burden, greater use of cosmetics and personal care products, and higher exposures in the occupational setting. Phthalate exposure in women has been associated with early menopause, decreased ovarian follicle counts, reduced egg yield, increased early pregnancy loss, and reduced clinical pregnancies and live births. Concurrently, phthalate exposure has also been associated with metabolic dysfunction including obesity, metabolic syndrome, and fatty liver disease. Unfortunately, the mechanisms underlying these associations are not understood and make preventative or therapeutic actions challenging. We developed a phthalate-treated mouse model in which exposure to human relevant levels of phthalates replicates phenotypes associated with phthalate exposures in humans. Using toxicoproteomic and lipidomic approaches we show that antral follicles from these mice have dysregulated abundance of lipid metabolism proteins, high intrafollicular saturated free fatty acids, and high intrafollicular acylcarnitine content. We propose to test the overall hypothesis that phthalate mixture exposure leads to stimulated fatty acid synthesis with concurrent inhibition of fatty acid oxidation. We propose that these effects are mediated via changes in the transcription of fatty acid synthesis and oxidation proteins through dysregulated LXR-SREBP1c and PPAR signaling pathways, and that persistent, long-term exposure to phthalate mixtures will lead to metabolic and reproductive disorders in our mouse model. Our hypothesis will be tested via completion of three specific aims designed to identify the relevant tissues and molecular events leading to phthalate-induced elevated intrafollicular free fatty acids (Aim1) and acylcarnitines (Aim 2), and identify which known reprometabolic phenotypes associated with phthalates in humans are replicated by long-term exposure to epidemiologically-based phthalate mixtures in our mouse model. Our findings will provide unique insight into the interplay between systemic and ovarian effects of phthalates.