Epigenetic Changes After Intrauterine Exposure to Endocrine Disrupting Chemicals

描述(由申请人提供) 候选人是流行病学家和生物统计学家，在进行以人口为基础的观察研究方面有10年的经验。申请书描述了一项为期3年的职业发展计划，该计划将为应聘者提供必要的正式培训和实验室研究经验，使其成为宫内化学品暴露和慢性病表观遗传流行病学的独立调查员。候选人的长期职业目标是开发一项结合流行病学、分子和表观遗传学原理的学术研究计划，研究癌症病因中基因、其表达和环境因素之间的复杂关联。培训部分包括一名环境癌症生物学家的指导和每年在环境遗传学和表观遗传学实验室为期六个月的轮换，此外还有正规的课程工作教育。研究部分描述了对怀孕期间收集的母亲尿液中内分泌干扰物(EDC)水平的前瞻性调查，以及与子代脐带血中生长因子的甲基化和印记状态以及Era基因的甲基化状态的关系。据推测，在宫内暴露于合成的内分泌细胞，包括双酚A和邻苯二甲酸酯二(2-乙基己基)邻苯二甲酸酯(DEHP)，邻苯二甲酸二丁酯(DBF)和邻苯二甲酸丁基苄酯(BBP)，在环境中存在显著水平，导致胰岛素样生长因子2的印迹丢失和LIT1基因在染色体11p15上印迹控制区的低甲基化。进一步假设，宫内暴露于双酚A和邻苯二甲酸盐DEHP、DBP和BBP可诱导era基因的低甲基化，从而增加era的转录表达。将在疾病控制中心采集孕妇的尿样，并测量EDC水平。分娩时将采集脐带血样本，并将确定DNA甲基化和印迹状态。这一设计的特点包括最先进的暴露确定，足够的统计能力来检测基因表达的表观遗传控制中与暴露相关的变化，以及对潜在混杂变量的有效控制。

DESCRIPTION (provided by applicant) The candidate is an epidemiologist and biostatistician with 10 years experience in conducting population-based observational studies. The application describes a 3-year career development plan that will provide the candidate with the formal training and laboratory research experience necessary for her development as an independent investigator in epigenetic epidemiology of chemical exposures in utero and chronic diseases. The candidate's long-term career objective is to develop an academic program of research that combines epidemiologic, molecular, and epigenetic principles to study the complex associations of genes, their expression, and environmental factors in the etiology of cancer. The training component includes mentorship by an environmental cancer biologist and six-month rotations annually in an environmental genetics and epigenetics laboratory in additional to formal course work education. The research component describes a prospective investigation of endocrine-disrupting chemical (EDC) levels in maternal urine collected during pregnancy and relation to methylation and imprinting status of growth factors and methylation status of the ERa gene in cord blood from offspring. It is hypothesized that intrauterine exposure to synthetic EDCs including, bisphenol A and the phthalates di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBF), and butyl benzyl phthalate (BBP), present at significant levels in the environment, induces loss of imprinting of insulin-like growth factor 2 and hypomethylation of the imprinting control region of the LIT1 gene on chromosome 11p15. Further it is hypothesized that intrauterine exposure to bisphenol A and the phthalates DEHP, DBP, and BBP induces hypomethylation of the ERa gene and thereby increases ERa transcription expression. Urine samples of pregnant women will be collected and EDC levels will be measured at the Centers for Disease Control. Cord blood samples will be collected at delivery and DNA methylation and imprinting status will be determined. Features of this design include state-of-the art exposure ascertainment, sufficient statistical power to detect exposure-related variation in epigenetic control of gene expression, and efficient control for potential confounding variables.