Environmental Estrogen Induced Epigenetic Alteration of Uterine Stem Cells

环境雌激素诱导子宫干细胞的表观遗传改变

• 批准号: 8388459
• 负责人: Hugh Smith Taylor
• 金额: $ 41.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8388459
• 关键词: Adult; Affect; Animals; Breast; Cell Proliferation; Cell physiology; Cells; ChIP-seq; Chromatin; Data; Defect; Diethylstilbestrol; Disease; Dose; Endocrine Disruptors; Endocrine disruption; Endometrial; Endometrial Carcinoma; Endometrium; Environmental Estrogen; Epigenetic Process; Estradiol; Estrogen Receptors; Estrogens; Estrus; Ethinyl Estradiol; Exposure to; Extracellular Matrix; Female; Gene Expression; Genes; Genome; Growth; Human; In Vitro; Incidence; Invaded; Knowledge; Lead; Life; Measures; Mediating; Menstrual cycle; Menstruation; Methylation; Modeling; Molecular; Mus; Natural regeneration; Perinatal Exposure; Phenotype; Population; Precipitation; Preventive; Proliferating; Relative (related person); Replacement Therapy; Research Personnel; Response Elements; Rodent; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Tissues; Transplantation; Uterine Diseases; Uterus; Woman; base; bisphenol A; bisulfite; cell growth; design; developmental disease; endometriosis; estrogenic activity; exposed human population; fetal; in vivo; in vivo Model; progenitor; programs; reproductive; response; xenoestrogen

DESCRIPTION (provided by applicant): In humans, exposure to xenoestrogens such as diethylstilbestrol (DES) and bisphenol A (BPA) has been associated with developmental disorders of the female reproductive tract. The investigators have previously shown that fetal exposure to these agents alters the methylation of estrogen response elements (EREs) in the endometrium. The change in ERE methylation results in altered ERE occupancy by estrogen receptor (ER) in vivo and altered gene expression in response to estrogens throughout life. The uterine endometrium is replaced in each menstrual cycle or estrus cycle in humans or rodents, respectively. The investigators were the first to identify the stem cells that regenerate this tisse. As the epigenetic changes in estrogen response persist in the adult, they are likely to be encoded in the stem cells that regenerate the endometrium in each reproductive cycle. The investigators hypothesize that xenoestrogen exposure affects methylation of multiple EREs in uterine stem cells leading to altered estrogen sensitivity as an adult. To test this hypothesis the investigators will determine the extent of uterine ERE methylation in the entire genome after DES or BPA exposure as well as the effect of exposure to these agents on endometrial stem cell growth and estrogen response in vitro and in vivo. The specific aims include 1) the use of chromatin precipitation, massively parallel sequencing and bisulfite sequencing to determine if exposure leads to preferential methylation of multiple EREs and if this occurs in uterine stem cells; 2) determine if exposure leads to altered endometrial stem cell estrogen response in vitro; and 3) use of an in vivo model to determine if endometrial stem cells from exposed animals are more prone to endometriosis or endometrial cancer. These studies will test the hypothesis that methylation of EREs in uterine stem cells and resultant altered estrogen responsiveness will lead to an increased incidence of estrogen mediated disorders, thus providing an epigenetic mechanism for reproductive tract disease associated with xenoestrogen exposure. This model explains how a weak estrogen results in an estrogenic response disproportionate to its intrinsic estrogenic activity and how this epigenetic signal persists despite loss of endometrium in each reproductive cycle due to altered methylation in endometrial stem cells. PUBLIC HEALTH RELEVANCE: Stem cells regenerate the endometrial lining of the uterus which is shed with each menstrual period. These studies will determine if the effects of fetal environmental estrogen exposure are epigenetically encoded in the endometrial stem cells. Knowledge of the molecular and cellular mechanisms that underlie the effects of environmental estrogen exposure will allow the design of preventive and therapeutic strategies.

描述（由申请人提供）：在人类中，暴露于异种雌激素，例如二乙基苯甲酸酯（DES）和双酚A（BPA）与女性生殖道的发育障碍有关。研究人员先前已经表明，胎儿暴露于这些药物会改变子宫内膜中雌激素反应元件（ERE）的甲基化。 ERE甲基化的变化导致体内雌激素受体（ER）的占用率改变，并改变了基因表达对雌激素的响应。子宫内膜子宫内膜在每个月经周期或人类或啮齿动物中分别被替换。研究人员是第一个识别再生该提示的干细胞的人。随着成年人雌激素反应的表观遗传变化持续存在，它们可能在每个生殖周期中再生子宫内膜的干细胞中编码。研究人员假设异源性暴露会影响子宫干细胞中多个ERE的甲基化，从而导致雌激素敏感性改变。为了检验这一假设 研究人员将在DES或BPA暴露后确定整个基因组中的子宫甲基化程度，以及暴露于这些药物对子宫内膜干细胞生长和体内雌激素反应的影响。具体目的包括1）使用染色质沉淀，大规模平行测序和亚硫酸盐测序，以确定暴露是否导致多个ERE的优先甲基化以及子宫干细胞中是否发生这种情况； 2）确定暴露在体外是否导致子宫内膜干细胞雌激素反应改变； 3）使用体内模型来确定来自暴露动物的子宫内膜干细胞是否更容易发生子宫内膜异位症或子宫内膜癌。这些研究将检验以下假设：子宫干细胞中ERE的甲基化以及雌激素反应的改变将导致雌激素介导的疾病的发生率增加，从而提供了一种与甲烯雌激素相关的生殖道疾病的表观遗传机制。 该模型解释了弱雌激素如何导致雌激素反应与其内在的雌激素活性不成比例，以及该表观遗传信号如何持续，尽管由于子宫内膜干细胞中甲基化的改变，每个生殖循环中子宫内膜的丧失。 公共卫生相关性：干细胞再生子宫的子宫内膜衬里，每个月经期都会脱落。这些研究将确定胎儿环境雌激素暴露的影响是否在子宫内膜干细胞中表观遗传编码。了解环境雌激素暴露影响的分子和细胞机制的知识将允许设计预防和治疗策略。