Phthalate-Induced Dysregulation of Prostaglandin and Angiogenic Function During Ovulation in Women

PROJECT SUMMARY/ABSTRACT This ONES award will elucidate the mechanisms by which phthalates, a class of endocrine-disrupting chemicals, disrupt prostaglandin and angiogenic function during the critical period of ovulation. Further, intervention therapies will be established to alleviate phthalate-induced inhibition of ovulation and fertility, which is crucial for environmental and reproductive health as exposure to phthalates is unavoidable. Phthalates are incorporated in several common consumer, medical, housing, and personal care products leading to daily human exposure. However, little is known about the effects of environmentally relevant levels and mixtures of phthalates on ovulation, especially in women. This is alarming because defects in ovulation are the leading cause of female infertility. The abundant increase of prostaglandins in the ovary and the surge of new vasculature formation, via angiogenesis, are vital for ovulation and fertility. Preliminary data for this proposal are the first to show that an environmentally relevant phthalate mixture decreases the levels of prostaglandins and factors that drive angiogenesis in human and mouse ovarian samples. Further, the phthalate mixture decreased ovulation rates by 96% in mouse samples. These findings suggest that environmentally relevant phthalate exposure targets ovulatory prostaglandin and angiogenic action, which may cause infertility. Our compelling preliminary data also suggest that supplementation with cyclic adenosine monophosphate, a common cell signaling molecule, to human ovarian cells may rescue the phthalate-induced decreases in ovulatory prostaglandin production. A major strength of this proposal is our ability to mimic human exposure to phthalates by the use of environmentally relevant phthalate mixtures and human ovarian models. These models, as well as in vivo and in vitro mouse models, will be used to test the hypothesis that phthalates inhibit ovulatory prostaglandin production and function, leading to impaired angiogenesis and ovulatory failure/infertility. Specific Aim 1 will elucidate the mechanism by which phthalates decrease ovulatory prostaglandin levels. Specific Aim 2 will determine the deficiencies in angiogenesis, ovulation, and fertility caused by phthalate exposure. Specific Aim 3 will establish therapeutic targets for intervention of phthalate toxicity. These findings will advance environmental health sciences by providing mechanistic data establishing the impact of environmentally relevant phthalate mixture exposure on prostaglandin and angiogenic function, which are essential mediators for fertility. Thus, these findings will reveal novel actions of phthalates on infertility and reproductive dysfunction. Additionally, the use of human samples and the establishment of intervention therapies provide a translational approach to understanding and mitigating phthalate toxicities. Infertility in couples seeking to conceive leads to a decreased quality of life, including increased levels of stress, diminished social functioning, and mental and physical health issues in women. The overarching goal of this proposal is to provide a foundation to benefit women’s reproductive and general healthcare.