Phthalates and Ovarian Toxicity

邻苯二甲酸盐和卵巢毒性

• 批准号: 10163844
• 负责人: Jodi A. Flaws
• 金额: $ 35.29万
• 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/10163844
• 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; 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 outcome; 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巢卵泡的发展，以及原始卵泡对原代卵泡的恒定生长，然后是原发卵泡，最终是肛门卵泡，这是唯一能够释放出蛋白质和同步性性类固醇类固醇类固醇类固醇的卵泡的卵泡。由于出生时建立有限的卵巢储备，卵泡生长（卵泡发生）是一个不可逆转的过程，因此卵泡发生的异常调节可能具有不良的生殖意义。特别是，原始卵泡的加速耗竭，尤其是通过原始卵泡不规则地激活给原代卵泡，可能导致不育和早产卵巢衰竭。尽管卵泡发生对于生育和健康的重要性，但我们对控制卵泡从原始阶段到主要阶段的生长的环境因素知之甚少。我们的初步数据表明，邻苯二甲酸酯（DEHP）及其主要的代谢物单（2-乙基己基）苯甲酸酯（MEHP）加速小鼠中卵泡的内分泌内分泌及其主要代谢物单（2-乙基己基）。此外，我们的初步数据表明，DEHP失去调节卵泡发生的途径的关键成分水平，磷酸肌醇3-激酶（PI3K）信号传导途径。这些数据令人关注，因为邻苯二甲酸盐是人类组织中存在的最污染物之一，并且它们存在于无数的消费产品，个人护理产品，农药，木材饰面，粘合剂，粘合剂，溶剂，润滑剂，润滑剂，调味剂和医用设备中。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无处不在的邻苯二甲酸盐的无处不在，我们建议使用小鼠测试邻苯二甲酸酯的假设，即暴露于邻苯二甲酸盐及其代谢物及其代谢物加速了卵巢卵形植物的质孕期，通过Pi3k和相关的病态和相关的导致了渗透性和相关性。 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代谢物，3）确定邻苯二甲酸酯诱导的卵泡发生加速是否导致不育症和早产卵巢衰竭。总的来说，拟议的工作将确定邻苯二甲酸酯引起卵巢毒性和雌性哺乳动物的生殖功能障碍的机制。反过来，这可能导致发展邻苯二甲酸酯诱导疾病的新靶标。