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

邻苯二甲酸盐引起的女性排卵期间前列腺素和血管生成功能失调

• 批准号: 10358879
• 负责人: Patrick Ryan Hannon
• 金额: $ 42.73万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358879
• 关键词: Address; Agonist; Angiogenic Factor; Animal Model; Award; Biological Assay; Blood capillaries; Cell Proliferation; Cell model; Cells; Chemicals; Couples; Cyclic AMP; Cyclooxygenase Inhibitors; Data; Defect; Dose; Endocrine Disruptors; Endothelial Cells; Ensure; Environmental Health; Environmental Impact; Exhibits; Exposure to; FGF2 gene; Failure; Female infertility; Fertility; Fertility Rates; Foundations; Functional disorder; Goals; Healthcare; Housing; Human; Impairment; In Vitro; Infertility; Link; Literature; Mediator of activation protein; Medical; Mental Health; Metabolism; Modeling; Mus; Nature; Non-Steroidal Anti-Inflammatory Agents; Oocytes; Outcome; Ovarian; Ovarian Follicle; Ovarian Granulosa Cell; Ovary; Ovulation; Ovulation Inhibition; PTGS2 gene; Parents; Pathway interactions; Pregnant Women; Prevalence; Process; Production; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Public Health; Quality of life; Reproductive Health; Research; Rodent Model; Sampling; Signal Transduction; Signaling Molecule; Social Functioning; Societies; Stress; Supplementation; Testing; Time; Toxic effect; VEGFA gene; Woman; Women' s Health; Work; angiogenesis; cost; critical period; exposed human population; granulosa cell; human model; in vivo; migration; mouse model; novel; personal care products; phthalates; physical conditioning; prevent; receptor; reproductive; translational approach; urinary

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.

项目摘要/摘要 该奖项将阐明邻苯二甲酸化学物质的邻苯二甲酸化学物质的机制 在关键排卵期间破坏前列腺素和血管生成功能。此外，救援方法 将研究以减轻邻苯二甲酸酯引起的排卵和生育抑制作用，这对于 由于暴露于邻苯二甲酸盐的环境和生殖健康是不可避免的。邻苯二甲酸盐纳入 几种常见的消费者，医疗，住房和个人护理产品，导致每日人类接触。 但是，关于环境相关水平和邻苯二甲酸盐混合的影响知之甚少 排卵，尤其是在女性中。这令人震惊，因为排卵的缺陷是女性的主要原因 不育。通过 血管生成，对于排卵和生育至关重要。该提案的初步数据是第一个证明 与环境相关的邻苯二甲酸酯混合物降低了前列腺素和驱动因素的水平 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了排卵率 小鼠样品中的96％。这些发现表明与环境相关的邻苯二甲酸盐暴露目标 排卵前列腺素和血管生成作用，可能导致不育症。我们引人入胜的初步数据 表明补充循环腺苷单磷酸（一种常见的细胞信号分子）至 人类卵巢细胞可以挽救排卵前列腺素和血管生成的邻苯二甲酸酯诱导的下降 因子水平。该提议的主要优势是我们通过使用模仿人类对邻苯二甲酸盐的暴露的能力 与环境相关的邻苯二甲酸酯混合物和人类卵巢模型的组成。这些模型以及体内和 体外小鼠模型将用于测试邻苯二甲酸抑制排卵前列腺素的假设 生产和功能，导致血管生成和排卵衰竭受损。具体目标1将 阐明邻苯二甲酸降低排卵前列腺素水平的机制。具体目标2将 确定邻苯二甲酸盐引起的血管生成，排卵和生育能力的缺乏。特定目标3将定义 减轻邻苯二甲酸盐毒性的方法。这些发现将通过 提供机械数据，以建立与环境相关的邻苯二甲酸酯混合物暴露对 前列腺素和血管生成功能，它们是生育能力的必要介体。那就是这些发现将揭示 邻苯二甲酸盐对不育症和生殖功能障碍的新作用。另外，使用人类样品 救援方法的建立提供了一种转化方法来理解和缓解 邻苯二甲酸盐的毒性。寻求怀孕的妇女不孕症会导致生活质量下降，包括 压力水平增加，社会功能减少以及身心健康问题。通过描绘 邻苯二甲酸盐暴露对排卵和生育的有害影响，该提案的总体目标是 为了使妇女的生殖和一般医疗保健提供基础。