Epidemiology & epigenetics: Maternal diet, DNA methylation, & offspring adiposity

描述（由研究者提供）：该申请涉及挑战领域08，“基因组学”和挑战主题08- ag -105（也称为OD [OBSSR] - 102），“研究关键发育时期个体行为、社会和物理环境以及遗传/表观遗传过程之间相互作用的方法”。几十年的动物生理学实验明确地表明，在早期、可塑的、关键的发育时期受到干扰，会对慢性心脏代谢疾病（如肥胖、血压和葡萄糖耐受不良）和寿命本身产生终身的、有时是不可逆转的不利影响。最近，表观遗传学领域揭示了这些观察结果背后的一些机制。例如，在黄鼠模型中，母体在受孕前后富含甲基供体的饮食会导致亚稳态外等位基因的DNA甲基化，从而防止后代变得肥胖、糖尿病和易患癌症。然而，没有一项针对人类群体的研究考察了从怀孕早期母体饮食到表观遗传变化到后代表型的途径。本研究的目的是研究妊娠早期产妇饮食之间的关系，特别是甲基供体摄入量的变化，妊娠早期和晚期产妇血液和脐带血中的整体DNA甲基化，以及3岁和7岁儿童的肥胖相关结局。我们将在具有良好特征的产前队列研究项目Viva中开展该项目，该项目可能是美国唯一的具有设计特征的流行病学研究，以满足以下目标：前瞻性收集，验证，妊娠早期饮食信息，孕产妇和脐带血标本，以及研究质量的后代心脏代谢表型数据。肥胖、心血管疾病、糖尿病及相关疾病是美国发病率和死亡率的主要原因，其最早的起源存在于产前的行为和环境中。将表观遗传学数据添加到现有的流行病学研究中，有可能将动物实验的知识转化为人类状况，并进行预防性干预。考虑到潜在的科学和公共卫生影响，现在是时候投入大量资金，以显著的方式迅速推进这一领域，而挑战赠款计划提供了合适的工具。

DESCRIPTION (provided by investigator): This application addresses Challenge Area 08, "Genomics," and Challenge Topic 08-AG-105 (also OD [OBSSR] - 102), "Approaches to study the interactions among individual behaviors, social and physical environments, and genetic/epigenetic processes during critical developmental periods." Decades of animal physiology experiments unequivocally show that perturbations during early, plastic, critical periods of development can have lifelong, sometimes irreversible adverse impact on markers of chronic cardio- metabolic disease like adiposity, blood pressure and glucose intolerance, and on lifespan itself. The field of epigenetics has recently revealed some of the mechanisms underlying these observations. For example, in the yellow agouti mouse model, a maternal diet rich in methyl donors around conception causes DNA methylation of a metastable epiallele, preventing offspring from becoming fat, diabetic, and cancer-prone. No study in human populations, however, has examined pathways from maternal diet in early pregnancy through epigenetic changes to offspring phenotype. The goals of this study are to examine relationships among maternal diet in early pregnancy, particularly variation in intake of methyl donors, global DNA methylation in maternal blood in early and late pregnancy and in umbilical cord blood, and adiposity-related outcomes in 3- and 7-year-old children. We will carry out this project within the well-characterized pre-birth cohort study Project Viva, which is perhaps the only US-based epidemiologic study with the design features to address these aims: prospectively collected, validated, early pregnancy diet information, maternal and cord blood specimens, and research- quality offspring cardio-metabolic phenotype data. Obesity, cardiovascular disease, diabetes, and related conditions are leading causes of morbidity and mortality in the U.S., and their earliest origins exist in behavior and environment during the prenatal period. Adding epigenetic data to existing epidemiologic studies offers the potential to translate knowledge from animal experiments to the human condition as well as to mount preventive interventions. Given the potential scientific and public health impact, the time has come for an influx of funds to advance this area in significant ways quickly, and the Challenge Grants program provides the right vehicle to do so. PUBLIC HEALTH RELEVANCE: The goals of this study are to examine the extent to which maternal diet in early pregnancy affects methylation of maternal and fetal DNA, an epigenetic process; and the extent to which DNA methylation predicts obesity and cardiovascular risk factors in 3- and 7-year-old children. The importance of this research is two-fold. First is knowledge acquisition--the potential to translate findings from animal experiments to the human condition. Second is public health importance-- optimizing maternal diet in early pregnancy could improve the health of the next generation.