Phthalate Exposure and Female Reproductive Aging

邻苯二甲酸盐暴露与女性生殖衰老

• 批准号: 10576477
• 负责人: Jodi A. Flaws
• 金额: $ 54.34万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576477
• 关键词: Acceleration; Acute; Adhesives; Adult; Age; Aging; Anti-Inflammatory Agents; Aryl Hydrocarbon Receptor; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Aging; Cell Count; Cells; Cessation of life; Characteristics; Childbirth; Chronic; Curcumin; Data; Defoaming Agents; Delayed Childbearing; Development; Disadvantaged; Disease; Dose; Endocrine Disruptors; Environment; Exposure to; Female; Fertility; Fibrosis; Follicle Stimulating Hormone; Foundations; Gene Expression; Gene Expression Profiling; Greater sac of peritoneum; Growth; Health; Hormones; Hypothalamic structure; IL8 gene; ITGAM gene; Immune; Immunohistochemistry; Infertility; Inflammasome; Inflammation; Inflammatory; Interferons; Interleukin-10; Interleukin-6; KISS1 gene; Lubricants; Macrophage; Medical Device; Menopausal Symptom; Mental Depression; Mus; Natural Killer Cells; Osteoporosis; Ovarian Follicle; Ovary; Pathway interactions; Peritoneal Macrophages; Pesticides; Physiological; Pituitary Gland; Play; Population; Premature Menopause; Proliferating; Public Health; Publishing; RANTES; Reporter; Reproduction; Reproductive Health; Risk; Role; Serum; Signal Pathway; Solvents; System; T-Lymphocyte; Testing; Time; Tissues; Uterus; Woman; Women' s Health; Wood material; Work; angiogenesis; antagonist; cardiovascular disorder risk; consumer product; cytokine; diminished ovarian reserve; early experience; early onset; environmental chemical; epidemiology study; experience; exposed human population; female reproductive system; human tissue; improved; inhibin B; men; mono-(2-ethylhexyl)phthalate; novel; personal care products; phthalates; protein expression; reproductive; reproductive longevity; reproductive senescence; subfertility

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.

女性生殖系统比任何其他生理系统都要衰老，这使得它是最敏感的。 老化的指示器。大多数女性在51岁左右经历生殖衰老，但许多女性 经历早期生殖衰老(绝经早期)。这是一个严重的公共卫生问题，因为很早 生殖老化与早发不孕症和增加患多种疾病的风险有关。 死亡。此外，早期生殖衰老的后果对推迟生育的女性来说是显著的 出于个人和职业原因而生孩子。尽管早期生殖老化对 在妇女健康方面，人们对导致早期生殖老化的机制知之甚少。我们出版的和 初步数据表明，急性接触环境化学品邻苯二甲酸二(2-乙基己基)酯(DEHP) 和邻苯二甲酸二异松酯(DiNP)，成年期会增加早期生殖衰老的几个关键指标 在雌性小鼠身上。此外，已发表的数据表明，炎症小体的激活和炎症是 生殖老化的特征和我们的初步数据表明，接触DEHP会增加炎症性 下丘脑巨噬细胞、DEHP和DiNP暴露增加大鼠炎症途径的表达 卵巢，和DEHP激活腹膜腔内常驻的巨噬细胞。此外，已发表的研究 提示芳烃受体(AhR)在调节生殖衰老和 我们的初步数据表明，DEHP及其代谢物(MEHP)可诱导已知AhR靶点的表达 一种特异的AhR拮抗剂可以从邻苯二甲酸盐诱导的卵泡中拯救卵泡 抑制卵泡生长。邻苯二甲酸盐暴露的这些影响令人担忧，因为邻苯二甲酸盐是 人体组织中存在的最大污染物，它们存在于无数的消费品中，个人 护理产品、农药、木器饰面、粘合剂、溶剂、润滑剂、消泡剂和医疗用品 设备。鉴于我们的初步数据，生殖老龄化对生殖健康的重要性，以及 由于人类无处不在地接触邻苯二甲酸盐，我们建议用小鼠来检验这一假设：环境 相关剂量的DEHP和DiNP与AhR途径相互作用，引起炎症并促进早期 生殖衰老。为了验证这一假设，我们将完成以下具体目标：1)比较 发病时与慢性暴露于环境相关剂量的DEHP和DiNP的比较 生殖老化的特征，2)确定与环境相关的邻苯二甲酸盐暴露是否会导致 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 会导致早期的生殖衰老。总的来说，建议的研究将大大提高我们对 邻苯二甲酸盐暴露导致女性早期生殖衰老的机制。反过来，这项工作将设置 寻找和开发治疗邻苯二甲酸酯类药物的新靶点的基础 疾病，包括早期生殖衰老。