Phthalate-Induced Ovulatory Dysfunction in Women

项目总结/摘要 这个K99/R 00奖项将为帕特里克汉农博士的独立研究生涯做好准备，其主要目标是 为Hannon博士提供所有必要的技术和专业技能，以过渡到学术界的职业生涯 成为生殖毒理学领域的领导者汉农博士在阐明方面接受过广泛的培训 在啮齿动物模型中环境毒物对卵巢的影响，但在这个K99/R 00中，他将扩大他的 研究培训并将这些发现转化为人类健康和生育力。这些目标将会实现 在Hannon博士热情而出色的指导团队的支持下，由托马斯咖喱博士和 汉弗莱·姚。由Hannon博士在指导下创建的研究计划和职业发展计划 他的导师团队将为汉农博士提供新的实验技术和技能， 独立的研究项目。在研究培训部分，汉农博士将阐明 以及邻苯二甲酸盐（一类干扰内分泌的化学物质）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到邻苯二甲酸盐， 邻苯二甲酸酯被引入到无数的普通消费品、医疗品、建筑品和个人护理品中。 然而，人们对环境中邻苯二甲酸酯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，因为排卵缺陷是不孕症的主要原因， 妇女该提案的初步数据首次表明，环境相关的邻苯二甲酸酯 混合物抑制孕酮（P4）的产生，并改变P4受体（PGR）、前列腺素- 人绒毛膜促性腺激素后内过氧化物合酶2（PTGS 2）和双调蛋白（AREG） 治疗（hCG;类似于周期中期促黄体激素激增）在人类和小鼠卵巢细胞。P4， PGR、PTGS 2和AREG是已知的排卵介质。因此，这些研究结果表明，邻苯二甲酸酯 暴露可能会破坏排卵，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酯通过改变 导致排卵和生育能力受损的排卵介质。具体目标1（指导阶段）将确定 邻苯二甲酸酯暴露会影响排卵。具体目标2（指导和独立 阶段）将阐明邻苯二甲酸酯损害这些排卵过程的机制。具体目标3 （独立阶段）将确定邻苯二甲酸酯暴露导致体内排卵障碍和不孕症。 这些发现将确定邻苯二甲酸酯对女性生育力和生殖健康的影响，同时提供 博士汉农为他的学术生涯提供了必要的研究和专业技能。此外，实现 对人体样本中邻苯二甲酸酯作用机制的更深入了解将开始提供 邻苯二甲酸酯引起的生殖功能障碍和不孕症的干预途径。

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.