Epigenetic trajectories in early childhood following perinatal parental stress – insights from the DREAM study

越来越多的证据表明，母亲在怀孕期间的压力水平对孩子的发育有持久的影响。在这方面，表观遗传信号，如DNA甲基化，已经成为解释产前母体应激(PNMS)如何深入皮肤的核心机制。重要的是，到目前为止，这一领域的少数表观遗传学研究大多依赖于对PNMS的广泛回顾测量或在出生时或出生后不久评估表观遗传学状态。为了解决这一差距，德累斯顿关于父母养育、工作和心理健康的研究(Dresdner Studie zu Elternschaft，Arbeit and Mentaler Gesundheit)非常适合描述产前和出生后父母压力暴露对儿童发展的纵向影响的生物路径。Dream研究于2017年6月启动，是一项前瞻性队列研究，包括总共N=3865人，希望孩子在从怀孕后期到产后4.5年的过程中从心理、社会、临床和生物水平评估围产期压力，并计划延长到童年中期。虽然之前的大多数表观遗传学研究都集中在PNMS的严重形式上，但梦想研究的一个明确目的是调查一个被广泛忽视的PNMS的来源，即(怀孕)母亲工作相关压力的作用。此外，DREAM研究将进一步评估多个PNMS暴露对胎儿表观基因组的综合影响。虽然在PNMS研究中，父亲(成为)的作用被广泛忽视，但父母双方的压力暴露评估具有显著的优势，例如，为了将PNMS的影响与共同遗传易感性的影响区分开来。综上所述，该项目旨在检验这样一种假设，即总体上累积的PNMS和特定的工作相关压力会引发幼儿(∼4.5年)表观遗传学变化的纵向轨迹，进而预测早期健康结果。为此，我们将从先前关于PNMS、内化症状、皮质醇输出和表观遗传老化的表观基因组关联研究的汇总统计中估计应激相关表观遗传风险分数(ERS)。使用这种ERS反映了一种强大的策略，将单个基因座的微小影响聚集在一起，然后可以用来有力地预测健康表型。作为第二个目标，我们试图评估PNMS和出生后第一年父母应激对各自ERS的独立和综合影响。拟议项目的第三个目标是调查在接触PNMS后，ERS是否调节与压力相关的健康结果的变化(例如，急性和长期皮质醇输出、内化症状)。深入了解胎儿健康和疾病根源的分子途径现在已成为高度优先考虑的公共卫生问题，其长期目标是提供循证预防战略。

Accumulating evidence suggests that a mother’s stress level during pregnancy has lasting effects on the development of her child. In this regard, epigenetic signatures such as DNA methylation have emerged as central mechanisms explaining how prenatal maternal stress (PNMS) may get under the skin. Importantly, the few epigenetic studies in this field so far mostly rely on broad retrospective measures of PNMS or assess the epigenetic state at or shortly after birth. To address this gap, the Dresden Study on Parenting, Work, and Mental Health (DREAM; “DResdner Studie zu Elternschaft, Arbeit und Mentaler Gesundheit”) is ideally suited to delineate biological pathways by which prenatal and early postnatal parental stress exposures longitudinally impact on child development. Launched in June 2017, the DREAM study is a prospective cohort study including a total of N = 3,865 individuals expecting a child to assess perinatal stress on a psychological, social, clinical, and biological level during the course from late pregnancy to 4.5 years postpartum, with planned extension into middle childhood. While most prior epigenetic studies focused on severe forms of PNMS an explicit aim of the DREAM study is to investigate a widely neglected source of PNMS, namely the role of work-related stress of the (expectant) mothers. In addition, the DREAM study will further allow to evaluate combined effects of multiple PNMS exposures on the fetal epigenome. While the role of the (becoming) father has been widely neglected in PNMS studies, the assessment of stress exposure in both parents posits a significant strength, e.g., in order to disentangle the effects of PNMS from those of the shared genetic susceptibility. In summary, this project aims to test the hypothesis that cumulative PNMS in general and work-related stress in specific provoke a longitudinal trajectory of epigenetic changes in young children (∼4.5 years) that, in turn, predict early health outcomes. To this end, we will estimate stress-related epigenetic risk scores (ERS) derived from summary statistics of prior epigenome-wide association studies on PNMS, internalizing symptoms, cortisol output, and epigenetic aging. Use of such ERS reflects a powerful strategy to aggregate small effects of single loci, which can then serve to robustly predict health phenotypes. As a secondary goal, we seek to evaluate independent and combined effects of PNMS and early postnatal parental stress during the first years of life on respective ERS. A third goal of the proposed project is to investigate whether ERS mediate changes in stress-related health outcomes (e.g., acute and long-term cortisol output, internalizing symptoms) following exposure to PNMS. Providing an in-depth understanding of the molecular pathways underlying fetal origins of health and disease has now become a public health concern of high priority with the long-term goal of delivering evidence-based prevention strategies.