Epigenetic Effects of Prenatal Arsenic Exposure and Fetal Growth

描述(由申请人提供)：Molly Kile，硕士，SCD，环境流行病学家，哈佛大学公共卫生学院副研究员。这份申请是为了K01导师职业发展奖，该奖项将正规教育、有组织的指导和培训与详细的研究计划相结合，使Kile博士能够成为一名独立的研究员，专门从事围产期环境流行病学研究，能够调查与产前接触环境化学品相关的表观遗传-环境相互作用。 流行病学和实验研究表明，宫内环境可能代表着对可能损害生长和器官发育的化学物质的生物敏感窗口，这些化学物质可能会导致日后的不良健康后果。虽然这些关系背后的机制尚不清楚，但已经假设与表观遗传失调有关。暴露人群中的前瞻性纵向出生队列是研究宫内化学物质暴露和表观遗传-环境相互作用的影响的最佳设计，这些影响可能导致终身表型变化。在该奖项中，Kile博士将使用从3个前瞻性纵向出生队列收集的数据，这些队列专门为评估产前金属暴露对围产期和儿科健康结果的影响而设计，以1)检查产前砷暴露与胎儿生长之间的关系；2)利用脐带白细胞和脐静脉内皮细胞，研究砷与内皮一氧化氮合酶(ENOS)和胰岛素样生长因子基因(Igf2)的DNA甲基化之间的相互作用；以及3)探索Igf2基因DNA甲基化与胎儿生长之间的关联。 Kile博士具备开展拟议研究的良好条件，因为她以前在分子环境流行病学方面的研究经验，以及她的导师团队提供的独特资源，包括获得3个大型已建立的预期纵向出生队列，这些队列将在此次获奖期间提供必要的暴露评估数据、遗传物质、新生儿测量和协变量数据；获得最先进的分子生物学实验室；以及围产期流行病学和表观遗传学的高级课程。拟议的人体研究将填补我们对砷毒性及其影响人类发育的潜在知识的重要研究空白，从而为临床和公共卫生干预提供信息。拟议的培训和职业发展将使基尔博士做出实质性的科学贡献，发展成为一名独立调查人员所需的知识和技能，并使她成为围产期环境流行病学领域的领导者。 公共卫生相关性：胎儿发育不良可导致低出生体重，这与发病率和死亡率增加有关。因此，了解导致胎儿不良生长的因素是公共卫生的优先事项。拟议的研究将填补我们对砷毒性及其对胎儿生长的影响方面的重要研究空白，可能为发展中国家和发达国家的临床和公共卫生干预提供信息。

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.