Prenatal stress and epigenetic programming of the HPA axis and autonomic balance

描述（由申请人提供）：压力已成为社会逆境对健康影响研究的中心概念。越来越多的证据表明，不利的胎儿环境会改变后代的生物行为应激反应，包括下丘脑-垂体-肾上腺（HPA）轴和自主神经系统（ANS）功能，这可能对健康产生长期影响。关于这些系统编程所涉及的底层过程，仍然存在许多问题。胎儿编程涉及发育可塑性，关键时期的环境干扰会改变细胞、器官系统和/或关键的体内平衡途径的结构和功能。在怀孕期间，母亲的经历和条件，包括压力，使胎儿暴露于可能诱发“胎儿编程”的激素和代谢线索。基因表达的表观遗传失调已经成为一种被广泛接受的基于胎儿的儿科和成人疾病的机制，尽管对人类的研究仍然很少。我们提出了一种互补的方法来阐明表观遗传学在这种情况下的作用，考虑到可能涉及婴儿应激反应编程的广泛途径。我们将以两种互补的方式研究甲基化，即选择的候选基因的DNA甲基化和全基因组发现。此外，编程效应可能通过出生时可接触的关键靶组织对产前代谢扰动的不同反应来介导，这些组织以前与产前压力和/或慢性疾病有关。利用哈佛代际压力机制规划（PRISM）研究，一个资助的产前队列研究，旨在研究产前母亲压力对婴儿压力反应和特应性风险的影响，我们建议收集3个目标组织（胎盘、脐带动脉、脐带白细胞）来开始研究这些关系。在PRISM研究的150对母婴中，我们将描述妊娠中期HPA轴功能（昼夜唾液皮质醇节律）和ANS功能（昼夜α淀粉酶反应）。出生时，我们将从3个目标组织（脐带血、胎盘、脐带动脉）中存档并提取基因组DNA。对于基因特异性通路目标，我们将检查候选基因的DNA甲基化是否与神经内分泌反应相关（GR, 11-2 HSD， BDNF）；ANS函数（NET， BDNF）；和炎症（iNOS, TNF1）与产前母亲应激（皮质醇和1-淀粉酶的昼夜轨迹）和6个月大婴儿应激反应（由唾液皮质醇和1-淀粉酶的昼夜节律以及HPA和ANS对实验室应激源的反应性指示）的生理相关。PRISM将作为我们甲基组学的发现集。为了重复我们的甲基组学研究结果，我们将使用墨西哥城ELEMENT研究的人群，对母亲和婴儿进行类似的评估。虽然提出了一些理论模型来解释社会条件如何“进入身体”以影响健康，但社会心理压力模型已被越来越多地采用。这项研究可能开始告诉我们这在最基本的层面上是如何发生的。

DESCRIPTION (provided by applicant): Stress has become a central construct in the study of health effects of social adversity. Growing evidence links an adverse fetal environment to altered biobehavioral stress responses in the offspring including the hypothalamic-pituitary adrenal (HPA) axis and autonomic nervous system (ANS) functioning which may have long-term implications on health. Many questions remain about the underlying processes involved in programming of these systems. Fetal programming involves developmental plasticity, where environmental disturbances during critical periods alter the structure and function of cells, organ systems and/or key homeostatic pathways. During pregnancy, maternal experiences and conditions, including stress, expose the fetus to hormonal and metabolic cues that may induce 'fetal programming'. Epigenetic dysregulation of gene expression has emerged as a widely accepted mechanism of fetal-based pediatric and adult disease albeit research in humans remains sparse. We propose a complimentary approach to elucidating the role of epigenetics in this context, given the wide array of pathways that may be involved in programming the infant stress response. We will investigate methylation in two complementary ways, i.e., DNA methylation of selected candidate genes and genome-wide discovery. Moreover, programming effects may be mediated by varied responses to prenatal metabolic perturbations in key target tissues accessible at time of birth and previously linked to prenatal stress and/or chronic disease. Leveraging the Harvard PRogramming of Intergenerational Stress Mechanisms (PRISM) study, a funded prenatal cohort designed to examine the influence of prenatal maternal stress on the infant stress response and atopic risk, we propose the collection of 3 target tissues (placenta, umbilical artery, cord white blood cells) to begin to examine these relationships. In 150 mother- infants pairs from the PRISM study, we will characterize HPA axis functioning (diurnal salivary cortisol rhythms) and ANS functioning (diurnal alpha amylase response) in mid-pregnancy. At birth, we will archive and extract genomic DNA from the 3 target tissues (umbilical cord blood, placentas, umbilical arteries). For gene-specific pathway aims we will examine whether DNA methylation in candidate genes related to the neuro-endocrine response (GR, 11-2 HSD, BDNF); ANS function (NET, BDNF); and inflammation (iNOS, TNF1) are associated with physiological correlates of prenatal maternal stress (diurnal cortisol and 1-amylase trajectories) and the infant stress response at age 6 months indexed by diurnal salivary cortisol and 1-amylase rhythms and HPA and ANS reactivity in response to an in-laboratory stressor. PRISM will serve as our discovery set for methylomics. To replicate our methylomics findings, we will use a population from the Mexico City ELEMENT study with similar assessments in mothers and infants. While a number of theoretical models explaining how social conditions "get into the body" to impact health have been proposed, the psychosocial stress model has been increasingly adopted. This study may begin to inform how this happens at the most basic level.