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

围产期父母压力后儿童早期的表观遗传轨迹——DREAM 研究的见解

• 批准号: 495984244
• 负责人: Professorin Dr. Nina Alexander, Ph.D.
• 金额: --
• 依托单位: Klinik und Poliklinik für Psychiatrie und Psychotherapie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/495984244?language=en
• 关键词: Epigenetic; trajectories; early; childhood; following

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.

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展有持久的影响。在这方面，DNA甲基化等表观遗传特征已成为解释产前母体压力（PNMS）如何进入皮肤的核心机制。重要的是，到目前为止，该领域的少数表观遗传学研究主要依赖于PNMS的广泛回顾性测量或评估出生时或出生后不久的表观遗传状态。为了解决这一差距，德累斯顿研究育儿，工作和心理健康（DREAM;“DRESSTUDIE ZU Elternschaft，Arbeit und Mentaler Gesundecraft”）是理想的适合描绘的生物途径，产前和产后早期父母的压力暴露纵向影响儿童的发展。DREAM研究于2017年6月启动，是一项前瞻性队列研究，共包括N = 3，865名期待孩子的人，以评估从妊娠晚期到产后4.5年期间的心理，社会，临床和生物学水平的围产期压力，并计划扩展到儿童中期。虽然大多数先前的表观遗传学研究集中在严重形式的PNMS，但DREAM研究的明确目的是调查一个被广泛忽视的PNMS来源，即（准）母亲的工作相关压力的作用。此外，DREAM研究将进一步评估多次PNMS暴露对胎儿表观基因组的综合影响。虽然（成为）父亲的角色在PNMS研究中被广泛忽视，但对父母双方压力暴露的评估表明了一个显着的优势，例如，以便将PNMS的影响与共有的遗传易感性的影响分开。总之，该项目旨在检验以下假设：一般而言，累积PNMS和具体的工作相关压力会引起幼儿（约4.5岁）表观遗传变化的纵向轨迹，进而预测早期健康结果。为此，我们将估计与压力相关的表观遗传风险评分（ERS），这些评分来自先前对PNMS、内化症状、皮质醇输出和表观遗传衰老的表观基因组关联研究的汇总统计。这种ERS的使用反映了一种强大的策略，可以聚合单个基因座的小效应，然后可以用于稳健地预测健康表型。作为第二个目标，我们试图评估独立的和综合的影响PNMS和早期产后父母的压力，在第一年的生活对各自的ERS。拟议项目的第三个目标是调查ERS是否介导与压力相关的健康结果的变化（例如，暴露于PNMS后的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起源的分子途径现已成为高度优先的公共卫生问题，其长期目标是提供循证预防战略。