Epigenetic Changes After Intrauterine Exposure to Endocrine Disrupting Chemicals

描述（由申请人提供） 候选人是一名流行病学家和生物统计学家，在开展基于人群的观察性研究方面有10年的经验。申请描述了一个为期3年的职业发展计划，将为候选人提供必要的正式培训和实验室研究经验，使其成为子宫内化学品暴露和慢性疾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制定一项学术研究计划，结合流行病学，分子和表观遗传学原理，研究基因，其表达和环境因素在癌症病因学中的复杂关联。培训内容包括环境癌症生物学家的指导，以及每年在环境遗传学和表观遗传学实验室进行为期六个月的轮换，以补充正式的课程工作教育。该研究部分描述了一项前瞻性调查，在怀孕期间收集的母亲尿液中的内分泌干扰化学品（EDC）水平，以及与后代脐带血中生长因子的甲基化和印记状态以及ER α基因的甲基化状态的关系。 据推测，宫内暴露于合成内分泌干扰物（包括双酚A和邻苯二甲酸二（2-乙基己基）酯（DEHP）、邻苯二甲酸二丁酯（DBF）和邻苯二甲酸丁基苄基酯（BBP））（在环境中存在显著水平）可诱导胰岛素样生长因子2印迹丢失和染色体11 p15上LIT 1基因印迹控制区的低甲基化。 此外，假设宫内暴露于双酚A和邻苯二甲酸酯DEHP、DBP和BBP诱导ER a基因的低甲基化，从而增加ER a转录表达。 将采集孕妇的尿液样本，并在疾病控制中心测量EDC水平。将在分娩时采集脐带血样本，并确定DNA甲基化和印迹状态。 该设计的特征包括最先进的暴露确定、足够的统计功效以检测基因表达的表观遗传控制中的确定性相关变异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.