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

项目总结/摘要 这个ONES奖将阐明邻苯二甲酸酯，一类内分泌干扰化学品， 在排卵的关键时期破坏前列腺素和血管生成功能。此外，救援方法 将研究减轻邻苯二甲酸酯诱导的排卵和生育抑制，这对 环境和生殖健康，因为接触邻苯二甲酸盐是不可避免的。邻苯二甲酸酯被纳入 几种常见的消费、医疗、住房和个人护理产品，导致人类每天接触。 然而，很少有人知道邻苯二甲酸酯的环境相关水平和混合物的影响， 排卵，尤其是女性。这是令人担忧的，因为排卵缺陷是女性不孕的主要原因。 不孕卵巢中大量增加的甘草素和新血管形成的激增，通过 血管生成，对排卵和生育至关重要。这项提议的初步数据首次表明， 环境相关的邻苯二甲酸酯混合物降低了三尖杉酯素的水平， 人和小鼠卵巢样品中的血管生成。此外，邻苯二甲酸酯混合物降低排卵率 96%的小鼠样本。这些发现表明，环境相关的邻苯二甲酸酯暴露目标 排卵前列腺素和血管生成作用，可能导致不孕。我们令人信服的初步数据也 提示补充一种常见细胞信号分子环磷酸腺苷， 人卵巢细胞可以挽救邻苯二甲酸酯诱导的排卵前列腺素和血管生成减少， 因素水平。该提案的一个主要优势是我们能够通过使用 环境相关的邻苯二甲酸酯混合物和人类卵巢模型。这些模型，以及体内和 体外小鼠模型将用于检验邻苯二甲酸酯抑制排卵前列腺素的假设 产生和功能，导致血管生成受损和排卵失败/不育。具体目标1将 阐明邻苯二甲酸酯降低排卵前列腺素水平的机制。具体目标2将 确定邻苯二甲酸酯引起的血管生成、排卵和生育能力的缺陷。具体目标3将定义 减轻邻苯二甲酸酯毒性的方法。这些发现将推动环境健康科学， 提供确定环境相关邻苯二甲酸酯混合物暴露对 前列腺素和血管生成功能，这是生育的基本介质。这些发现将揭示 邻苯二甲酸酯对不孕和生殖功能障碍的新作用。此外，使用人体样本 和建立救援方法提供了一个翻译的方法来理解和减轻 邻苯二甲酸酯毒性寻求怀孕的女性不孕症导致生活质量下降，包括 压力增加，社会功能下降，以及心理和身体健康问题。通过划定 邻苯二甲酸酯暴露对排卵和生育能力的不利影响，本提案的总体目标是 为妇女的生殖保健和一般保健奠定基础。

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, rescue approaches will be investigated 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 and angiogenic factor levels. 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 phthalates. Specific Aim 3 will define approaches to alleviate 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 rescue approaches provide a translational approach to understanding and mitigating phthalate toxicities. Infertility in women seeking to conceive leads to a decreased quality of life, including increased levels of stress, diminished social functioning, and mental and physical health issues. By delineating the detrimental impacts of phthalate exposure on ovulation and fertility, the overarching goal of this proposal is to provide a foundation to benefit women’s reproductive and general healthcare.