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: 10006568
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006568
• 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.

项目概要/摘要 该 K99/R00 奖项将为帕特里克·汉农 (Patrick Hannon) 博士的独立研究生涯做好准备，其主要目标是 为汉农博士提供过渡到学术界所需的所有技术和专业技能 并成为生殖毒理学领域的领导者。汉农博士在阐明问题方面接受过广泛的培训 环境毒物对啮齿动物模型卵巢的影响，但在这个 K99/R00 中，他将扩展他的研究 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 博士由 Drs. 领导的热情且出色的指导团队的支持下托马斯·库里和 汉弗莱·姚. Hannon博士指导下制定的研究计划和职业发展计划 他的指导团队将为汉农博士提供建立新的实验技术和技能 一个独立的研究计划。在研究培训部分，汉农博士将阐明其影响 邻苯二甲酸盐（一类内分泌干扰化学物质）损害排卵和生育能力的机制 在人类和啮齿动物中。育龄妇女每天都会接触邻苯二甲酸盐，因为 邻苯二甲酸盐广泛存在于众多普通消费品、医疗、建筑和个人护理产品中。 然而，人们对邻苯二甲酸盐环境相关水平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 女性。该提案的初步数据首次表明，与环境相关的邻苯二甲酸盐 混合物抑制黄体酮 (P4) 的产生并改变 P4 受体 (PGR)、前列腺素的 mRNA 水平 人绒毛膜促性腺激素后的内过氧化物合酶 2 (PTGS2) 和双调蛋白 (AREG) 对人类和小鼠卵巢细胞进行治疗（hCG；类似于周期中期黄体生成素激增）。 P4, PGR、PTGS2 和 AREG 是已知的排卵介质。因此，这些发现表明邻苯二甲酸酯 接触可能会扰乱排卵，导致不孕。原代人颗粒细胞模型和小鼠将 用于检验邻苯二甲酸盐通过改变邻苯二甲酸盐的水平对排卵过程产生不利影响的假设 排卵介质导致排卵和生育能力受损。具体目标 1（指导阶段）将确定 邻苯二甲酸盐暴露会损害哪些排卵事件。具体目标 2（指导和独立 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 （独立阶段）将确定邻苯二甲酸盐暴露会导致体内排卵受损和不孕。 这些发现将确定邻苯二甲酸盐对女性生育力和生殖健康的影响，同时提供 汉农博士的学术生涯所需的研究和专业技能。此外，达到 对人类样本中邻苯二甲酸盐的作用机制有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孕不育的途径。