Epigenetic Changes After Intrauterine Exposure to Endocrine Disrupting Chemicals

宫内暴露于内分泌干扰化学物质后的表观遗传变化

• 批准号: 7494025
• 负责人: KARIN B MICHELS
• 金额: $ 13.5万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-07 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494025
• 关键词: 11p15; Adult; Affect; Arts; Blood specimen; Breast Carcinoma; Cancer Etiology; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Chemical Exposure; Chromosomes; Chronic Disease; Complex; Confounding Factors (Epidemiology); CpG Islands; DNA Methylation; Development; Development Plans; Dibutyl Phthalate; Diethylhexyl Phthalate; Education; Embryonic Development; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiologist; Epidemiology; Epigenetic Process; Estrogens; Exposure to; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Transcription; Genome; Genomic Imprinting; Growth Factor; Hormones; Hypertension; Insulin-Like Growth Factor II; Investigation; Laboratories; Laboratory Research; Malignant Neoplasms; Mammary gland; Measures; Mentorship; Methylation; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Outcome; Phenotype; Population; Predisposition; Pregnancy; Pregnant Women; Promoter Regions; Rate; Research; Research Personnel; Risk; Rotation; Sampling; Signal Transduction; Source; Training; Translating; Umbilical Cord Blood; Urine; Variant; Work; base; bisphenol A; butylbenzyl phthalate; career; design; environment related cancer; environmental chemical; experience; imprint; in utero; malignant breast neoplasm; phthalate; phthalates; programs; prospective

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.

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，在进行基于人群的观察性研究方面具有10年的经验。该申请描述了一项为期3年的职业发展计划，该计划将为候选人提供她作为子宫和慢性疾病化学暴露表观遗传流行病学的独立研究者所必需的正式培训和实验室研究经验。候选人的长期职业目标是制定一项研究课程，结合了流行病学，分子和表观遗传学原理，以研究癌症病因中基因的复杂关联，其表达和环境因素。该培训组成部分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中进行六个月轮换的指导。该研究成分描述了对怀孕期间收集的母体尿液中的内分泌干扰化学水平（EDC）水平的前瞻性研究，以及与后代血液中ERA基因的甲基化和甲基化状态的关系和甲基化状态。 据推测，子宫内暴露于合成EDC中，包括双苯酚A和脑苯二甲酸甲酸酯（2-乙基己基）邻苯二甲酸酯（DEHP）（DEHP），邻苯二甲酸二丁酯（DBF）和丁基苯二甲酸丁酯（BBP），在环境中具有显着水平的损失，并在环境中的损失显着，并属于INSIUL的损失。 LIT1基因在11p15染色体上的印迹控制区域。 此外，假设宫内暴露于双苯酚A和邻苯二甲酸，DEHP，DBP和BBP会诱导ERA基因的低甲基化，从而增加ERA转录表达。 将收集孕妇的尿液样本，并将在疾病控制中心测量EDC水平。将在输送时收集脐带血样本，并确定DNA甲基化并确定烙印状态。 该设计的特征包括最先进的暴露确定性，足够的统计能力，可检测基因表达的表观遗传控制的暴露相关变化以及对潜在混杂变量的有效控制。