Phthalate Exposure and Female Reproductive Aging

女性生殖系统比其他任何生理系统都要早衰老，因此是最敏感的 老化的指标。大多数女性在51岁左右经历生殖衰老，但许多女性 经历早期生殖老化（早期绝经）。这是一个严重的公共卫生问题，因为早期 生殖老化与不孕症的早期发作和几种疾病的风险增加有关， 死亡此外，生育早期衰老的后果在延迟生育的妇女中是显著的。 出于个人和职业原因生育。尽管早期生殖衰老对人类的 妇女的健康，对早期生殖老化的机制知之甚少。我们的出版和 初步数据表明，急性暴露于环境化学品邻苯二甲酸二（2-乙基己基）酯（DEHP） 和邻苯二甲酸二异壬酯（DiNP），在成年期增加了早期生殖衰老的几个关键指标 在雌性小鼠中。此外，已发表的数据表明，炎性小体的活化和炎症是与炎症相关的。 生殖老化的标志，我们的初步数据表明，DEHP暴露增加炎症， 下丘脑中的巨噬细胞，DEHP和DiNP暴露增加了 卵巢，DEHP激活腹腔内的巨噬细胞。此外，已发表的研究 表明芳烃受体（AhR）在调节生殖衰老中起重要作用， 我们的初步数据表明，DEHP及其代谢物（MEHP）诱导已知AhR靶点的表达 在垂体和卵巢中，一种特异性AhR拮抗剂可以从邻苯二甲酸酯诱导的卵巢卵泡中拯救卵泡。 抑制卵泡生长。邻苯二甲酸酯暴露的这些影响值得关注，因为邻苯二甲酸酯是 人体组织中存在的最大污染物，它们存在于无数的消费品、个人 护理产品、杀虫剂、木材饰面、粘合剂、溶剂、润滑剂、防腐剂和医疗 装置.根据我们的初步数据，生殖老龄化对生殖健康的重要性， 人类普遍暴露于邻苯二甲酸盐，我们建议使用小鼠来测试环境 相关剂量的DEHP和DiNP与AhR通路相互作用，引起炎症并促进早期 生殖老化为了验证这一假设，我们将完成以下具体目标：1）比较 急性与慢性暴露于环境相关剂量的DEHP和DiNP， 生殖老化的特征，2）确定环境相关的邻苯二甲酸酯暴露是否会导致 炎症，导致早期生殖衰老，以及3）确定邻苯二甲酸酯是否通过AhR途径起作用 导致早期生殖老化。总的来说，拟议的研究将大大提高我们对 邻苯二甲酸酯暴露导致早期女性生殖衰老的机制。反过来，这项工作将设置 为识别和开发治疗邻苯二甲酸酯诱导的 疾病，包括早期生殖老化。

The female reproductive system ages before any other physiological system, making it the most sensitive indicator of aging. Most women experience reproductive senescence around age 51, but many women experience early reproductive aging (early menopause). This is a serious public health problem because early reproductive aging is associated with early onset of infertility and increased risk of several diseases and early death. Further, the consequences of early reproductive senescence are significant in women who delay childbirth for personal and professional reasons. Despite the profound impact of early reproductive aging on women’s health, little is known about the mechanisms underlying early reproductive aging. Our published and preliminary data indicate that acute exposure to the environmental chemicals, di-(2-ethyhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), during adulthood increases several key indicators of early reproductive aging in female mice. Further, published data indicate that activation of the inflammasome and inflammation are hallmarks of reproductive aging and our preliminary data indicate that DEHP exposure increases inflammatory macrophages in the hypothalamus, DEHP and DiNP exposure increase expression of inflammatory pathways in the ovary, and DEHP activates resident macrophages in the peritoneal cavity. In addition, published studies indicate that the aryl hydrocarbon receptor (AhR) plays an important role in regulating reproductive aging and our preliminary data indicate that DEHP and its metabolite (MEHP) induce expression of the known AhR targets in the pituitary and the ovary and that a specific AhR antagonist rescues ovarian follicles from phthalate-induced inhibition of follicle growth. These impacts of phthalate exposure are of concern because phthalates are one of the top contaminants present in human tissues and they are present in a myriad of consumer products, personal care products, pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and medical devices. Given our preliminary data, the importance of reproductive aging for reproductive health, and the ubiquitous exposure of humans to phthalates, we propose to use mice to test the hypothesis that environmentally relevant doses of DEHP and DiNP interact with the AhR pathway to cause inflammation and facilitate early reproductive aging. To test this hypothesis, we will complete the following specific aims:1) compare the effects of acute versus chronic exposure to environmentally relevant doses of DEHP and DiNP on the onset and characteristics of reproductive aging, 2) determine if environmentally relevant phthalate exposure causes inflammation, leading to early reproductive aging, and 3) determine if phthalates work through the AhR pathway to cause early reproductive aging. Collectively, the proposed studies will greatly improve our understanding of the mechanisms by which phthalate exposure causes early female reproductive aging. In turn, this work will set the foundation for the identification and development of novel targets for the treatment of phthalate-induced diseases, including early reproductive aging.