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.

女性生殖系统在任何其他物理系统之前都会老化，使其成为最敏感的 衰老的指标。大多数女性在51岁左右经历复制感，但许多女性 体验早期生殖衰老（早期）。这是一个严重的公共卫生问题，因为 生殖衰老与早期不孕症的发作和多种疾病的风险增加有关 死亡。此外，早期生殖感受的后果在延迟的女性中很明显 出于个人和专业原因分娩。尽管早期衰老对 妇女的健康，对早期生殖衰老的基本机制知之甚少。我们出版的 初步数据表明急性暴露于环境化学物质，di-（2-乙基己基）苯甲酸盐（DEHP） 和邻苯二甲酸二苯二甲酸酯（DINP），在成年期间增加了早期生殖衰老的几个关键指标 在雌鼠中。此外，已发表的数据表明炎症体和炎症的激活是 生殖老化的标志和我们的初步数据表明DEHP暴露会增加炎症 下丘脑，DEHP和DINP暴露的巨噬细胞增加了炎症途径的表达 卵巢和DEHP激活腹膜腔中的巨噬细胞。此外，发表的研究 表明芳基烃受体（AHR）在控制生殖老化和 我们的初步数据表明DEHP及其代谢物（MEHP）影响已知的AHR靶标的表达 在垂体和卵巢中，特定的AHR拮抗剂从邻苯二甲酸酯引起的 抑制卵泡生长。邻苯二甲酸盐暴露的这些影响令人关注，因为邻苯二甲酸盐是 人体组织中存在的最污染物，它们存在于无数的消费产品中 护理产品，农药，木材饰面，粘合剂，解决方案，润滑剂，散剂剂和医疗 设备。鉴于我们的初步数据，生殖衰老对生殖健康的重要性以及 人类无处不在地暴露于邻苯二甲酸盐，我们建议使用小鼠测试以下假设 相关剂量的DEHP和DINP与AHR途径相互作用，引起感染并促进 生殖衰老。为了检验这一假设，我们将完成以下特定目的：1）比较效果 急性与长期暴露于与环境相关剂量的DEHP和DINP的发作和DINP 生殖老化的特征，2）确定是否与环境相关的邻苯二甲酸盐暴露原因 炎症，导致早期生殖老化，3）确定邻苯二甲酸盐是否通过AHR途径起作用 引起早期生殖衰老。总的来说，拟议的研究将大大提高我们对 邻苯二甲酸盐暴露会导致早期女性生殖衰老的机制。反过来，这项工作将设定 鉴定和开发邻苯二甲酸酯诱导的新目标的基础 疾病，包括早期衰老。