Phthalate-Induced Ovulatory Dysfunction in Women

邻苯二甲酸盐引起的女性排卵功能障碍

• 批准号: 10241441
• 负责人: Patrick Ryan Hannon
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-02 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241441
• 关键词: Academia; Academic skills; Address; Age; Amphiregulin; Animal Model; Area; Award; Biological Assay; Cell model; Cells; Cosmetics; Data; Defect; Development Plans; Endocrine; Endocrine Disruptors; Event; Excipients; Exposure to; Female; Female infertility; Fertility; Fertility Disorders; Functional disorder; Gene Expression; Gene Proteins; Goals; Granulosa-Lutein Cells; Health; Healthcare; Human; Human Chorionic Gonadotropin; Impairment; In Vitro; Infertility; Intervention; Lead; Leukocytes; Literature; Luteinizing Hormone; Measurement; Mediating; Mediator of activation protein; Medical; Mentors; Messenger RNA; Methods; Modeling; Mus; Ovarian; Ovary; Ovulation; Phase; Plasticizers; Pregnant Women; Prevalence; Process; Production; Progesterone; Prostaglandin Production; Protein Analysis; Proteins; Public Health; Quality of life; Reproductive Health; Research; Research Proposals; Research Training; Rodent; Rodent Model; Sampling; Societies; Solvents; Techniques; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Training; Translating; Woman; analog; angiogenesis; base; career; career development; chemical group; cost; cyclooxygenase 2; exposed human population; female fertility; granulosa cell; human model; human tissue; in vivo; insight; migration; mouse model; novel; ovarian dysfunction; personal care products; phthalates; programs; receptor; reproductive; response; skills; urinary

PROJECT SUMMARY/ABSTRACT This K99/R00 award will prepare Dr. Patrick Hannon for an independent research career, with the main goal of providing Dr. Hannon all the necessary technical and professional skills to transition into a career in academia and become a leader in the field of reproductive toxicology. Dr. Hannon has extensive training in elucidating the effects of environmental toxicants on the ovary in rodent models, but in this K99/R00 he will expand his research training and translate these findings into human health and fertility. These goals will be accomplished with the support of Dr. Hannon's enthusiastic and exceptional mentoring team, led by Drs. Thomas Curry and Humphrey Yao. The research proposal and career development plan created by Dr. Hannon with the guidance of his mentoring team will provide Dr. Hannon with new experimental techniques and skills needed to establish an independent research program. In the research training component, Dr. Hannon will elucidate the effects and mechanisms by which phthalates, a class of endocrine-disrupting chemicals, impair ovulation and fertility in humans and rodents. Women of reproductive age are exposed to phthalates on a daily basis because phthalates are incorporated in a myriad of common consumer, medical, building, and personal care products. However, little is known about the effects of environmentally relevant levels of phthalates on ovulation, especially in humans. This is concerning because defects in ovulation are the leading cause of infertility in women. Preliminary data for this proposal are the first to show that an environmentally relevant phthalate mixture inhibits progesterone (P4) production and alters the mRNA levels of P4 receptor (PGR), prostaglandin- endoperoxide synthase 2 (PTGS2), and amphiregulin (AREG) following human chorionic gonadotropin treatment (hCG; analogous to the midcycle luteinizing hormone surge) in human and mouse ovarian cells. P4, PGR, PTGS2, and AREG are known mediators of ovulation. Thus, these findings suggest that phthalate exposure may disrupt ovulation contributing to infertility. A primary human granulosa cell model and mice will be utilized to test the hypothesis that phthalates adversely impact ovulatory processes by altering the levels of ovulatory mediators leading to impaired ovulation and fertility. Specific Aim 1 (Mentored Phase) will determine which ovulatory events are impaired by phthalate exposure. Specific Aim 2 (Mentored and Independent Phases) will elucidate the mechanisms by which phthalates impair these ovulatory processes. Specific Aim 3 (Independent Phase) will establish that phthalate exposure causes impaired ovulation and infertility in vivo. These findings will establish the impact of phthalates on female fertility and reproductive health, while providing Dr. Hannon the necessary research and professional skills for his academic career. Further, the attainment of a greater understanding of the mechanisms of action of phthalates in human samples will begin to provide avenues to intervene on phthalate-induced reproductive dysfunction and infertility.

项目摘要/摘要 这一K99/R00奖项将为帕特里克·汉农博士的独立研究生涯做好准备，主要目标是 为汉农博士提供一切必要的技术和专业技能，以过渡到学术界的事业 并成为生殖毒理学领域的领先者。汉农博士曾接受过广泛的澄清训练 环境毒物对啮齿动物模型卵巢的影响，但在这篇K99/R00中，他将扩展他的 研究、培训并将这些发现转化为人类健康和生育能力。这些目标将会实现 在Hannon博士热情而杰出的指导团队的支持下，由Thomas Curry博士和 汉弗莱·姚。汉农博士在指导下创建的研究建议和职业发展计划 将为汉农博士提供新的实验技术和技能 一个独立的研究项目。在研究培训部分，汉农博士将阐明这些影响 邻苯二甲酸盐，一种干扰内分泌的化学物质，影响排卵和生育的机制 在人类和啮齿动物身上。育龄妇女每天接触邻苯二甲酸盐是因为 邻苯二甲酸酯被用于各种常见的消费、医疗、建筑和个人护理产品中。 然而，人们对环境相关水平的邻苯二甲酸酯对排卵的影响知之甚少。 尤其是在人类身上。这是令人担忧的，因为排卵缺陷是导致不孕的主要原因。 女人。这项提案的初步数据首次表明，一种与环境相关的邻苯二甲酸盐 合剂抑制孕酮(P4)的产生，改变P4受体(PGR)、前列腺素-1(PGE-1)的mRNA水平。 人绒毛膜促性腺激素后的内源性过氧化物合成酶2(PTGs2)和两调节素(AREG) 人和小鼠卵巢细胞的治疗(hCG；类似于周期中期黄体生成素激增)。P4， PGR、Ptgs2和AREG是已知的排卵调节因子。因此，这些发现表明邻苯二甲酸盐 暴露可能会扰乱排卵，导致不孕不育。一种原代人类颗粒细胞模型和小鼠 被用来检验这样的假设：邻苯二甲酸盐通过改变血清中的 排卵中介物导致排卵和生育能力受损。具体目标1(指导阶段)将决定 哪些排卵事件会因邻苯二甲酸盐暴露而受损。具体目标2(辅导型和独立型 阶段)将阐明邻苯二甲酸盐损害这些排卵过程的机制。具体目标3 (独立期)将确定邻苯二甲酸盐暴露在体内会导致排卵障碍和不孕。 这些发现将确定邻苯二甲酸酯对女性生育和生殖健康的影响，同时提供 汉农博士为他的学术生涯提供了必要的研究和专业技能。此外，实现 对邻苯二甲酸盐在人体样本中的作用机制的更深入的了解将开始提供 干预邻苯二甲酸盐引起的生殖功能障碍和不育的途径。