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: 10544036
• 负责人: Patrick Ryan Hannon
• 金额: $ 42.87万
• 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/10544036
• 关键词: Agonist; Angiogenesis Inhibition; 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; Environment; Environmental Health; 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; 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; Proliferating; Prostaglandin Inhibition; 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.

项目概要/摘要 该 ONES 奖项将阐明邻苯二甲酸盐（一类内分泌干扰化学物质）的机制， 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 将进行研究以减轻邻苯二甲酸盐引起的排卵和生育抑制，这对于生育至关重要 环境和生殖健康，因为接触邻苯二甲酸盐是不可避免的。邻苯二甲酸盐被纳入 几种常见的消费品、医疗、住房和个人护理产品会导致人类日常接触。 然而，人们对环境相关水平和邻苯二甲酸盐混合物对环境的影响知之甚少。 排卵，尤其是女性。这是令人震惊的，因为排卵缺陷是女性不孕的主要原因 不孕症。卵巢中前列腺素的大量增加和新血管形成的激增，通过 血管生成对于排卵和生育至关重要。该提案的初步数据首次表明 与环境相关的邻苯二甲酸盐混合物会降低前列腺素和驱动因素的水平 人类和小鼠卵巢样本中的血管生成。此外，邻苯二甲酸酯混合物降低了排卵率 在小鼠样本中提高了 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，可能导致不孕。我们令人信服的初步数据还 建议补充环磷酸腺苷（一种常见的细胞信号分子） 人类卵巢细胞可以挽救邻苯二甲酸盐引起的排卵前列腺素和血管生成的减少 因素水平。该提案的主要优点是我们能够通过使用来模拟人类接触邻苯二甲酸盐的情况 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，将用于测试邻苯二甲酸盐抑制排卵前列腺素的假设 生产和功能，导致血管生成受损和排卵失败/不孕。具体目标 1 将 阐明邻苯二甲酸盐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陷。具体目标 3 将定义 减轻邻苯二甲酸盐毒性的方法。这些发现将通过以下方式推进环境健康科学 提供机械数据，确定与环境相关的邻苯二甲酸酯混合物暴露对人体的影响 前列腺素和血管生成功能，它们是生育能力的重要介质。因此，这些发现将揭示 邻苯二甲酸盐对不孕症和生殖功能障碍的新作用。此外，使用人体样本 救援方法的建立为理解和减轻影响提供了一种转化方法 邻苯二甲酸盐毒性。寻求怀孕的女性不孕会导致生活质量下降，包括 压力增加、社会功能减弱以及精神和身体健康问题。通过描绘 邻苯二甲酸盐暴露对排卵和生育能力的有害影响，该提案的总体目标是 为有利于妇女的生殖和一般保健奠定基础。