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.

女性生殖系统先于任何其他生理系统衰老，使其成为最敏感的系统 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 经历早期生殖衰老（早期更年期）。这是一个严重的公共卫生问题，因为早期 生殖衰老与不孕症的早期发生以及多种疾病和早期疾病风险的增加有关。 死亡。此外，对于延迟生育的女性来说，早期生殖衰老的后果是严重的。 出于个人和职业原因分娩。尽管早期生殖衰老对 女性健康方面，人们对早期生殖衰老的机制知之甚少。我们出版的和 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），在成年期间会增加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，炎症小体的激活和炎症是 生殖衰老的标志和我们的初步数据表明，DEHP 暴露会增加炎症 下丘脑中的巨噬细胞、DEHP 和 DiNP 暴露会增加炎症通路的表达 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）在调节生殖衰老和 我们的初步数据表明 DEHP 及其代谢物 (MEHP) 诱导已知 AhR 靶标的表达 在垂体和卵巢中，特定的 AhR 拮抗剂可将卵泡从邻苯二甲酸盐诱导的 抑制卵泡生长。邻苯二甲酸盐暴露的这些影响值得关注，因为邻苯二甲酸盐是 人体组织中存在的主要污染物，它们存在于无数的消费品、个人产品中 护理产品、杀虫剂、木器漆、粘合剂、溶剂、润滑剂、消泡剂和医疗 设备。根据我们的初步数据，生殖衰老对生殖健康的重要性以及 由于人类普遍接触邻苯二甲酸盐，我们建议使用小鼠来检验环境 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 生殖衰老。为了检验这个假设，我们将完成以下具体目标：1）比较效果 急性与慢性暴露于环境相关剂量的 DEHP 和 DiNP 的发病率和 生殖衰老的特征，2) 确定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，3) 确定邻苯二甲酸盐是否通过 AhR 途径发挥作用 导致生殖早衰。总的来说，所提出的研究将极大地提高我们对 邻苯二甲酸盐暴露导致女性早期生殖衰老的机制。反过来，这项工作将设定 为识别和开发治疗邻苯二甲酸盐引起的新靶点奠定了基础 疾病，包括早期生殖衰老。