Epigenetic Effects of Prenatal Arsenic Exposure and Fetal Growth

产前砷暴露和胎儿生长的表观遗传效应

• 批准号: 7771313
• 负责人: Molly L Kile
• 金额: $ 10.2万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7771313
• 关键词: Address; Adrenal Gland Neoplasms; Adult; Animals; Area; Arsenic; Arts; Award; Bangladesh; Biological; Birth; Blood Vessels; Blood flow; Carcinogens; Cardiovascular Diseases; Cells; Characteristics; Chemical Exposure; Chemicals; Childhood; Clinical; DNA; DNA Methylation; Data; Developed Countries; Development; Dose; Economics; Education; Endothelial Cells; Environment; Environmental Epidemiology; Environmental Pollutants; Environmental Risk Factor; Epidemiologic Studies; Epidemiologist; Epidemiology; Epigenetic Process; Exposure to; Fetal Growth; Fetus; Genes; Genetic; Genetic Materials; Gestational Age; Growth; Growth Factor Gene; Growth and Development function; Health; Human; Human Development; IGF2 gene; Insulin-Like Growth Factor II; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leukocytes; Life; Liver; Low Birth Weight Infant; Lung; Measurement; Mentors; Mentorship; Metabolic; Metal exposure; Methylation; Mexico; Molecular; Mollies; Morbidity - disease rate; Mus; Newborn Infant; Nitric Oxide; Nutritional; Oklahoma; Organ; Outcome; Ovary; Oxygen; Parents; Perinatal; Perinatal Epidemiology; Placenta; Population; Positioning Attribute; Postdoctoral Fellow; Public Health; Public Health Schools; Recruitment Activity; Research; Research Personnel; Resources; Risk; Small for Gestational Age Infant; Somatomedins; Structure; Tars; Tissues; Toxic effect; Training; Umbilical Cord Blood; Umbilical cord structure; Umbilical vein; career development; cohort; cost effective; design; drinking water; environmental chemical; experience; human NOS2A protein; imprint; in utero; indexing; mortality; neurodevelopment; nutrition; prenatal; prenatal exposure; programs; prospective; public health priorities; public health relevance; research study; skills; toxicant; Address; Adrenal Gland Neoplasms; Adult; Animals; Area; Arsenic; Arts; Award; Bangladesh; Biological; Birth; Blood Vessels; Blood flow; Carcinogens; Cardiovascular Diseases; Cells; Characteristics; Chemical Exposure; Chemicals; Childhood; Clinical; DNA; DNA Methylation; Data; Developed Countries; Development; Dose; Economics; Education; Endothelial Cells; Environment; Environmental Epidemiology; Environmental Pollutants; Environmental Risk Factor; Epidemiologic Studies; Epidemiologist; Epidemiology; Epigenetic Process; Exposure to; Fetal Growth; Fetus; Genes; Genetic; Genetic Materials; Gestational Age; Growth; Growth Factor Gene; Growth and Development function; Health; Human; Human Development; IGF2 gene; Insulin-Like Growth Factor II; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Leukocytes; Life; Liver; Low Birth Weight Infant; Lung; Measurement; Mentors; Mentorship; Metabolic; Metal exposure; Methylation; Mexico; Molecular; Mollies; Morbidity - disease rate; Mus; Newborn Infant; Nitric Oxide; Nutritional; Oklahoma; Organ; Outcome; Ovary; Oxygen; Parents; Perinatal; Perinatal Epidemiology; Placenta; Population; Positioning Attribute; Postdoctoral Fellow; Public Health; Public Health Schools; Recruitment Activity; Research; Research Personnel; Resources; Risk; Small for Gestational Age Infant; Somatomedins; Structure; Tars; Tissues; Toxic effect; Training; Umbilical Cord Blood; Umbilical cord structure; Umbilical vein; career development; cohort; cost effective; design; drinking water; environmental chemical; experience; human NOS2A protein; imprint; in utero; indexing; mortality; neurodevelopment; nutrition; prenatal; prenatal exposure; programs; prospective; public health priorities; public health relevance; research study; skills; toxicant

DESCRIPTION (provided by applicant): Molly Kile, MS, ScD is an environmental epidemiologist and a Research Associate at Harvard School of Public Health. This application is for a K01 Mentored Career Development Award combines formal education, structured mentorship and training with a detailed research plan that will allow Dr. Kile to become an independent investigator who specializes in perinatal environmental epidemiology capable of investigating epigenetic-environmental interactions associated with prenatal exposure to environmental chemicals. Epidemiological and experimental studies suggest that the intrauterine environment may represent a biologically sensitive window for chemicals that may impair growth and organ development that result in adverse health outcomes later in life. While the mechanisms behind these relationships are unclear, it has been hypothesized that epigenetic dysregulation is involved. Prospective longitudinal birth cohorts in exposed populations are the optimal design to study the effects of in utero chemical exposures and epigenetic- environmental interactions that could lead to life-long phenotypic changes. For this award, Dr. Kile will use data collected from 3 prospective longitudinal birth cohorts that were specifically designed to evaluate the effects of prenatal metal exposure on perinatal and pediatric health outcomes to 1) examine the association between prenatal arsenic exposure, a common environmental pollutant, and fetal growth; 2) investigate the interaction between arsenic and DNA methylation of endothelial nitric oxide gene (eNOS) and the insulin-like growth factor gene (Igf2) which are well characterized and involved in fetal growth and development using umbilical cord leukocytes and umbilical vein endothelials cells; and 3) explore the association between Igf2 gene DNA methylation and fetal growth. Dr. Kile is well positioned to carry out the proposed studies because of her prior research experience in molecular environmental epidemiology and the unique resources available through her mentorship team including access to 3 large established prospective longitudinal birth cohorts that will provide the necessary exposure assessment data, genetic material, newborn measurements and covariate data during this award period; access to state-of-the-art molecular biological laboratories; and, advanced coursework in perinatal epidemiology and epigenetics. The proposed human studies will fill important research gaps in our knowledge of arsenic toxicity and its potential to impact human development that can inform clinical and public health interventions. The proposed training and career development will enable Dr. Kile make substantial scientific contributions and develop the knowledge and skills necessary to become an independent investigator and position her to become a leader in the field of perinatal environmental epidemiology. Public Health Relevance: Adverse fetal growth can lead to low birthweight which is associated with increased morbidity and mortality. As such, understanding the factors that contribute to adverse fetal growth is a public health priority. The proposed studies will fill important research gaps in our knowledge of arsenic toxicity and its impact on fetal growth that could inform both clinical and public health interventions in developing and developed countries.

描述（由申请人提供）：MOLLY KIL，MS，SCD是哈佛大学公共卫生学院的环境流行病学家和研究助理。该应用程序是针对K01指导的职业发展奖，将正规的教育，结构化指导和培训与详细的研究计划结合在一起，该计划将使Kile博士成为一名独立研究者，他专门研究能够调查与环境化学物质相关的表观遗传 - 环境相互作用的能力。 流行病学和实验研究表明，宫内环境可能代表一个对化学物质的生物学敏感窗口，可能会损害生长和器官发育，从而导致生活后期不良健康结果。尽管这些关系背后的机制尚不清楚，但已假设涉及表观遗传失调。裸露人群中的前瞻性纵向出生队列是研究子宫化学暴露和表观遗传环境相互作用的最佳设计，可能导致终身表型变化。为了获得该奖项，Kile博士将使用从3个前瞻性纵向出生队列中收集的数据，这些数据是专门设计的，以评估产前金属暴露对围产期和小儿健康结果的影响至1）检查产前砷暴露，一种常见的环境污染物和胎儿生长和胎儿生长； 2）研究内皮一氧化氮基因（ENOS）的砷和DNA甲基化与胰岛素样生长因子基因（IGF2）的相互作用，这些基因（IGF2）具有很好的特征，并使用脐带白细胞和脐带静脉内皮细胞参与了胎儿生长和发育； 3）探索IGF2基因DNA甲基化与胎儿生长之间的关联。 Kile博士在拟议的研究方面擅长进行拟议的研究，因为她先前在分子环境流行病学方面的研究经验以及通过她的指导团队获得的独特资源，包括访问3个大型已建立的前瞻性纵向出生同龄人，这些纵向分娩群体将提供必要的接触评估数据，遗传材料，新生儿测量和新奖励期间的数据；获得最先进的分子生物实验室；以及围产期流行病学和表观遗传学的高级课程。拟议的人类研究将填补我们对砷毒性的了解及其影响人类发展的潜力，这可以为临床和公共卫生干预提供依据。拟议的培训和职业发展将使Kile博士能够做出实质性的科学贡献，并发展成为独立研究者所必需的知识和技能，并将她定位为围产期环境流行病学领域的领导者。 公共卫生相关性：不良胎儿的生长会导致低出生体重，这与发病率和死亡率的增加有关。因此，了解导致不利胎儿增长的因素是公共卫生的重点。拟议的研究将填补我们对砷毒性及其对胎儿生长的影响的重要研究空白，这可以为发展中国家和发达国家的临床和公共卫生干预提供依据。