Phthalates and Ovarian Toxicity

邻苯二甲酸盐和卵巢毒性

• 批准号: 9767139
• 负责人: Jodi A. Flaws
• 金额: $ 35.31万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767139
• 关键词: 3-Phosphoinositide Dependent Protein Kinase-1; Acceleration; Acute; Adhesives; Adult; Age; Antral; Birth; Cardiovascular Diseases; Cessation of life; Chemicals; Child; Chronic; Complex; Cosmetics; Data; Defoaming Agents; Development; Diethylhexyl Phthalate; Disease; Dose; Endocrine Disruptors; Environmental Risk Factor; Exposure to; FRAP1 gene; Female; Fertility; Fertilization; Functional disorder; Gonadal Steroid Hormones; Growth; Health; Hormones; In Vitro; Infertility; Lead; Lubricants; Mammals; Medical Device; Menopausal Symptom; Messenger RNA; Metabolic; Mus; Osteoporosis; Outcome; Ovarian; Ovarian Follicle; Ovary; PTEN gene; Pathway interactions; Pesticides; Phosphatidylinositols; Phosphotransferases; Plasticizers; Premature Menopause; Premature Ovarian Failure; Primordial Follicle; Process; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Reproduction; Risk; Series; Signal Pathway; Solvents; Testing; Time; Toy; Woman; Wood material; Work; consumer product; design; egg; experimental study; exposed human population; female fertility; folliculogenesis; human tissue; improved; in vivo; inhibitor/antagonist; innovation; men; mono-(2-ethylhexyl)phthalate; novel; ovarian reserve; ovotoxicity; personal care products; phthalates; premature; recruit; reproductive; reproductive senescence; therapy development; transcriptome sequencing

Female fertility depends on the development of an adequate number of healthy primordial ovarian follicles as well the constant growth of primordial follicles to primary follicles then to pre-antral follicles and eventually to antral follicles, which are the only follicles capable of releasing an egg for fertilization and synthesizing sex steroid hormones. Because a finite ovarian reserve is established at birth and follicular growth (folliculogenesis) is an irreversible process, aberrant regulation of folliculogenesis can have adverse reproductive implications. In particular, accelerated depletion of primordial follicles, particularly through irregular activation of primordial follicles to primary follicles, can result in infertility and premature ovarian failure. Despite the importance of folliculogenesis for fertility and health, we know very little about the environmental factors that control the growth of follicles from the primordial to primary stage. Our preliminary data indicate that the endocrine disrupting chemical di(2-ethylhexyl) phthalate (DEHP) and its primary metabolite mono(2-ethylhexyl) phthalate (MEHP) accelerate folliculogenesis in mice. Further, our preliminary data indicate that DEHP dysregulates the levels of key components of a pathway that regulates folliculogenesis, the phosphoinositide 3-kinase (PI3K) signaling pathway. These data 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 normal fertility for reproductive and non-reproductive health, and the ubiquitous exposure of humans to phthalates, we propose to use mice to test the hypothesis that exposure to phthalates and their metabolites accelerates ovarian folliculogenesis through the PI3K pathway and related pathways, leading to infertility and premature ovarian failure. To test this hypothesis, we propose the following three specific aims: 1) determine if environmentally relevant doses of phthalates (DEHP, MEHP, and a phthalate mixture) accelerate ovarian folliculogenesis via the PI3K pathway and related pathways, 2) determine if the ovary has the capacity to respond to phthalate metabolites and to metabolize DEHP and the phthalate mixture into toxic metabolites, and 3) determine if phthalate-induced acceleration of folliculogenesis leads to infertility and premature ovarian failure. Collectively, the proposed work will determine the mechanisms by which phthalates cause ovarian toxicity and reproductive dysfunction in female mammals. In turn, this may lead to the development of novel targets for the treatment of phthalate-induced diseases.

女性的生育能力取决于足够数量的健康原始卵泡的发育，以及原始卵泡不断生长为初级卵泡，然后为窦前卵泡，最终为窦卵泡，窦卵泡是唯一能够释放卵子进行受精的卵泡并合成性类固醇激素。由于出生时就建立了有限的卵巢储备，并且卵泡生长（卵泡发生）是一个不可逆的过程，因此卵泡发生的异常调节可能会对生殖产生不利影响。特别地，原始卵泡的加速消耗，特别是通过原始卵泡不规则地激活为初级卵泡，可导致不孕和卵巢早衰。尽管卵泡发生对于生育和健康很重要，但我们对控制卵泡从原始阶段到初级阶段生长的环境因素知之甚少。我们的初步数据表明，内分泌干扰化学物质邻苯二甲酸二（2-乙基己基）酯（DEHP）及其主要代谢物邻苯二甲酸单（2-乙基己基）酯（MEHP）可加速小鼠的卵泡生成。此外，我们的初步数据表明，DEHP 会失调调节卵泡发生的途径的关键成分的水平，即磷酸肌醇 3-激酶 (PI3K) 信号途径。这些数据令人担忧，因为邻苯二甲酸盐是人体组织中存在的最主要污染物之一，并且存在于无数消费品、个人护理产品、杀虫剂、木器涂料、粘合剂、溶剂、润滑剂、消泡剂和医疗设备中。鉴于我们的初步数据、正常生育能力对生殖和非生殖健康的重要性以及人类普遍接触邻苯二甲酸盐，我们建议使用小鼠来检验这样的假设：接触邻苯二甲酸盐及其代谢物通过 PI3K 途径加速卵巢卵泡发生及相关途径，导致不孕和卵巢早衰。为了检验这一假设，我们提出以下三个具体目标：1) 确定环境相关剂量的邻苯二甲酸盐（DEHP、MEHP 和邻苯二甲酸盐混合物）是否通过 PI3K 途径和相关途径加速卵巢卵泡生成，2) 确定卵巢是否具有对邻苯二甲酸酯代谢物作出反应以及将 DEHP 和邻苯二甲酸酯混合物代谢成有毒代谢物的能力，以及 3) 确定邻苯二甲酸酯是否会诱导卵泡发生加速导致不孕和卵巢早衰。总的来说，拟议的工作将确定邻苯二甲酸盐引起雌性哺乳动物卵巢毒性和生殖功能障碍的机制。反过来，这可能会导致开发治疗邻苯二甲酸盐引起的疾病的新靶点。