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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

基本信息

批准号：
8528662
负责人：
Hugh Smith Taylor
金额：
$ 39.5万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8528662
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

项目摘要

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.

描述（由申请人提供）：在人类中，暴露于异雌激素如己烯雌酚（DES）和双酚A （BPA）与女性生殖道发育障碍有关。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（EREs）的甲基化。ERE甲基化的改变导致体内雌激素受体（ER）占据ERE的改变，以及一生中对雌激素的基因表达改变。在人类和啮齿类动物中，子宫内膜分别在每次月经周期和发情周期中被替换。研究人员是第一个确定再生组织的干细胞。由于雌激素反应的表观遗传变化在成人中持续存在，它们可能被编码在每个生殖周期中再生子宫内膜的干细胞中。研究人员假设，暴露于异种雌激素会影响子宫干细胞中多个雌激素受体的甲基化，从而导致成人雌激素敏感性的改变。为了验证这个假设