Prenatal stress and diet, and the fetal epigenome

母亲压力和饮食与胎儿表观基因组 摘要 在儿童中，包括躯干肥胖、高血糖和高脂血症在内的一系列代谢功能障碍是 发病率增加，不成比例地影响少数群体，并增加了长期不利的风险， 长期成果。虽然遗传因素是这种增加的基础，但这些条件也有很大的影响。 环境组成部分。在可疑的环境因素中，产前压力因素包括 与不良童年经历相关的母亲抑郁、焦虑和慢性压力; 其机制仍然知之甚少。基因和子宫内环境相互作用的一种方式是， 是通过表观遗传修饰引发疾病的。事实上，环境暴露，如社会 压力可以导致可检测的长期变化的途径，有助于食欲和饱腹感，营养 获得、代谢和脂肪沉积。然而，这些靶向的表观基因组区域 压力源仍然不清楚，主要是因为可用的基因组规模的阵列数据是在DNA衍生的 但表观遗传标记因细胞类型而异，所测量的细胞 类型可能与代谢功能障碍无关。但父母的胞嘧啶甲基化标记除外 控制基因组印记，称为印记控制区（ICR）。这些区域的甲基化是 在组织规范之前早期建立，因此在组织间相似。ICR异常甲基化 在外周血中可检测到的是与许多代谢性疾病有关的，这使得ICR成为有希望的靶点， 代谢性疾病的研究。直到最近，只有24个ICR是已知的，限制了这些ICR的范围。 调查事务所我们的研究小组最近确定了控制DNA甲基化标记的完整库， 基因组印记;在这里，我们试图利用这些ICR来识别与 儿童代谢功能障碍。我们将检验产前压力大大增加风险的假设 儿童心脏代谢功能障碍，以及可检测的表观遗传干扰在ICR介导 这些协会。我们还将评估抗炎饮食（如地中海饮食）在多大程度上- 风格饮食改变这些影响。我们将利用现有队列资源中的数据和生物样本 新生儿表观遗传学研究和怀孕期间的压力与健康，其中超过750名妇女和她们的 对怀孕3个月的儿童进行了跟踪，现在儿童的年龄从2岁到15岁不等。我们将 检验这一假设，即产前地中海式饮食，通过以下方式减轻产前压力对健康的影响： 表观遗传机制这将提供急需的关于社会压力因素的表观遗传指纹的数据 儿童代谢结果的集群，为专注于饮食控制的临床试验铺平了道路 以减轻各种产前暴露的影响。

Maternal stress and diet, and the fetal epigenome Abstract In children, a cluster of metabolic dysfunction including truncal obesity, hyperglycemia, and hyperlipidemia are increasing in prevalence, disproportionately affect minority populations, and increase the risk for adverse long- term outcomes. While genetic factors underlie some of this increase, these conditions also have a large environmental component. Among suspected environmental contributors are prenatal stressors including maternal depression and anxiety and chronic stress associated with adverse childhood experiences; the underlying mechanisms remain poorly understood. One way in which genes and the in utero environment can interact to trigger the initiation of disease is through epigenetic modifications. In fact, environmental exposures like social stress can cause detectable long-term changes in pathways that contribute to appetite and satiety, nutrient acquisition, metabolism, and fat deposition. However, the regions of the epigenome that are targeted by these stressors remains unclear, primarily because available genome-scale array data are measured in DNA derived from accessible tissues, such as blood—but epigenetic marks vary widely by cell type, and the measured cell types may not be relevant to metabolic dysfunction. The exception is parent-of origin cytosine methylation marks that control genomic imprinting, known as imprint control regions (ICRs). Methylation of these regions is established early, before tissue specification, and therefore is similar across tissues. Aberrant methylation of ICRs detectable in peripheral blood is implicated in numerous metabolic diseases, making ICRs promising targets for investigations of metabolic diseases. Until recently, only 24 ICRs were known, limiting the scope of these investigations. Our group recently identified the complete repertoire of DNA methylation marks that control genomic imprinting; here, we seek to leverage these ICRs to identify methylation patterns associated with metabolic dysfunction in children. We will test the hypothesis that prenatal stress substantially increases the risk of cardiometabolic dysfunction among children, and that detectable epigenetic perturbations at ICRs mediate these associations. We also will evaluate the extent to which anti-inflammatory diets such as the Mediterranean- style diet modify these effects. We will leverage data and biological samples from our existing cohort resources of the Newborn Epigenetics Study and Stress and Health In Pregnancy, where more than 750 women and their children have been followed from 3 months gestation, and children now range in age from 2 to 15 years. We will test the hypothesis that a Mediterranean-style diet prenatally, mitigates health effects of prenatal stress via epigenetic mechanisms. This will provide much-needed data on the epigenetic fingerprint linking social stressors to the cluster of metabolic outcomes in children, paving the way for clinical trials focused on dietary manipulation to mitigate the effects of a wide variety of prenatal exposures.