Epigenetic mechanisms of prenatal environmental stressors and offspring obesity risk

项目总结 在美国，儿童肥胖是一个主要的公共卫生问题，种族/民族差距和健康状况日益扩大 在整个生命过程中产生的后果。儿童肥胖的不平等可以追溯到早在婴儿期， 意味着产前可能是一个关键的窗口，在此期间环境差异 暴露可能会导致后代肥胖风险的差异。少数族裔的比例不成比例 受到不利环境条件的负担，如邻里层面的心理社会压力源和空气 污染物，这可能会协同作用，影响儿童肥胖的风险。理清各种影响 产前环境暴露和更好地了解这些暴露的机制 影响心脏代谢风险因素，如儿童肥胖，可能会导致慢性病风险的改善 评估和更有效的干预战略，特别是在 更有可能经历不利的环境。表观遗传机制-基因组的改变不会 修改DNA序列-在关键时期对环境暴露敏感，并可用作 这可能与儿童肥胖的早期生活差异有关。以前的研究发现，产前 心理社会应激源和环境毒物与表观遗传修饰有关，特别是在 DNA甲基化和后代肥胖风险，但没有考虑这些环境的联合影响 暴露和潜在的生物介体还没有被很好地理解。拟议的研究将 调查孕期环境压力是否通过以下途径影响子女肥胖风险 使用种族差异出生队列研究的数据对DNA甲基化进行修改，并对 童年。通过独立之路奖，候选人将获得额外的培训 环境暴露、生物标志物和表观遗传机制、生物信息学和专业 开发成功地过渡到专注于早期生命起源的独立研究职业 慢性病。在培训阶段获得的技能将用于：1)评估 产前社区心理社会应激源(集中贫困、剥夺、种族居住 隔离、暴力犯罪)和空气污染暴露对后代出生体重、生长轨迹的影响 12个月，以及3-5岁超重和肥胖的风险；2)检查产前的影响 邻里心理社会应激源和空气污染对子代脐带DNA甲基化的影响 血液；以及3)检查与环境应激源相关的DNA甲基化标记之间的关联 目标2中确定的儿童超重或肥胖风险。完成培训和研究目标 将产生科学报告和出版物，初步数据，以成功竞争R01资金， 并独特地定位候选人，为相关表观遗传学图谱的研究做出重大贡献 环境应激源对儿童肥胖风险的影响。

PROJECT SUMMARY Childhood obesity is a major public health issue in the U.S. with widening racial/ethnic gaps and health consequences across the life course. Inequalities in childhood obesity can be traced to as early as infancy, signifying the prenatal period as potentially a critical window during which differences in environmental exposures may program disparities in offspring obesity risk. Racial/ethnic minorities are disproportionately burdened by adverse environmental conditions, such as neighborhood-level psychosocial stressors and air pollutants, which may act synergistically to impact childhood risk of obesity. Disentangling the effects of prenatal environmental exposures and better understanding the mechanisms through which these exposures influence cardiometabolic risk factors, such as childhood obesity, may lead to improved chronic disease risk assessment and more effective intervention strategies, particularly among vulnerable populations who are more likely to experience adverse environments. Epigenetic mechanisms—changes to the genome that do not modify the DNA sequence—are sensitive to environmental exposures during critical periods and may serve as a putative link to early life disparities in childhood obesity. Previous studies have found that prenatal psychosocial stressors and environmental toxicants are associated with epigenetic modifications, particularly in DNA methylation, and offspring obesity risk, but have not considered the joint effect of these environmental exposures and the underlying biological mediators are not well understood. The proposed research will investigate whether environmental stressors during pregnancy influence offspring obesity risk through modifications in DNA methylation using data from a racially diverse birth cohort study with follow-up into childhood. Through the Pathway to Independence Award, the candidate will gain additional training in environmental exposures, biomarkers and epigenetic mechanisms, bioinformatics, and professional development to successfully transition into an independent research career focused on the early life origins of chronic disease. The skills acquired during the training phase will be used to: 1) Estimate the impact of prenatal neighborhood psychosocial stressors (concentrated poverty, deprivation, racial residential segregation, and violent crime) and air pollution exposure on offspring birth weight, growth trajectory in the first 12 months, and risk of overweight and obesity at 3-5 years of age; 2) Examine the effect of prenatal neighborhood psychosocial stressors and air pollution on offspring DNA methylation marks in umbilical cord blood; and 3) Examine the association between environmental stressor-related DNA methylation marks identified in Aim 2 and risk of childhood overweight or obesity. Completion of the training and research aims will result in scientific presentations and publications, preliminary data to successfully compete for R01 funding, and uniquely position the candidate to make significant contributions to the study of epigenetic profiles relating environmental stressors to childhood obesity risk.