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

产前应激、HPA 轴的表观遗传编程和自主平衡

• 批准号: 8466376
• 负责人: Rosalind J Wright
• 金额: $ 71.53万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466376
• 关键词: Adopted; Adrenal Glands; Adult; Affect; Age; Amylases; Animals; Archives; Autonomic nervous system; Biological; Birth; Blood Vessels; Blood flow; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cell physiology; Child; Childhood; Chronic Disease; Cities; Collection; Complex; Cues; Cytosine; DNA; DNA Methylation; Data; Disease; Endocrine; Enrollment; Environment; Environmental Risk Factor; Epigenetic Process; Equilibrium; Fetus; Funding; Future; Gene Expression; Genes; Genomics; Guanine Nucleotides; Health; Hormonal; Hormones; Human; Human Development; Hydrocortisone; Hypersensitivity; Hypothalamic structure; Immune; Infant; Inflammation; Inflammatory; Knowledge; Laboratories; Leukocytes; Life; Link; Maternal-Fetal Exchange; Measures; Mediating; Mediation; Mental disorders; Metabolic; Methylation; Mexico; Modeling; Modification; Molds; Mothers; Nervous System Physiology; Neurosecretory Systems; Newborn Infant; Pathway interactions; Physiological; Pituitary Gland; Placenta; Play; Population; Poverty; Pregnancy; Process; Prospective Studies; Psychological Stress; Psychosocial Stress; Regulator Genes; Reporting; Research; Risk; Role; Salivary; Sampling; Site; Social Conditions; Staging; Stress; Structure; Structure of umbilical artery; System; TNF gene; Theoretical model; Time; Tissues; Toxicology; Umbilical Cord Blood; Work; alpha-amylase; base; biobehavior; biological adaptation to stress; body system; cohort; critical period; design; developmental plasticity; disorder risk; early life exposure; epigenome; experience; fetal; fetal programming; genome-wide; hypothalamic-pituitary-adrenal axis; immune function; in utero; indexing; intergenerational; maternal stress; offspring; prenatal; prenatal influence; prenatal stress; programs; psychobiologic; response; social; stressor

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.

描述（由申请人提供）：压力已成为研究社会逆境对健康影响的核心概念。越来越多的证据表明，不良的胎儿环境与后代生物行为应激反应的改变有关，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。关于这些系统的编程所涉及的基本过程，仍然存在许多问题。胎儿编程涉及发育可塑性，其中关键时期的环境干扰改变细胞，器官系统和/或关键稳态途径的结构和功能。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导“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以胎儿为基础的儿科和成人疾病的机制，尽管在人类中的研究仍然很少。我们提出了一种补充的方法来阐明表观遗传学在这种情况下的作用，考虑到广泛的途径，可能参与编程的婴儿压力反应。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，编程效应可能是通过对出生时可接近的关键靶组织中的产前代谢扰动的不同反应介导的，并且先前与产前应激和/或慢性疾病有关。利用哈佛的PRISM研究，一个受资助的产前队列研究，旨在检查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个靶组织（胎盘，脐动脉，脐带白色血细胞），开始检查这些关系。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）的特征。在出生时，我们将从3种靶组织（脐带血、胎盘、脐动脉）中存档并提取基因组DNA。对于基因特异性通路的目的，我们将检查候选基因中的DNA甲基化是否与神经内分泌反应相关（GR，11-2 HSD，BDNF）; ANS功能（NET，BDNF）;和炎症（iNOS，TNF 1）与产前母体压力的生理相关性有关（昼夜皮质醇和1-淀粉酶轨迹）和6个月龄时婴儿应激反应（以昼夜唾液皮质醇和1-淀粉酶轨迹为指标），淀粉酶节律以及HPA和ANS反应性对实验室内应激源的反应。PRISM将作为我们甲基化组学的发现集。为了复制我们的甲基组学研究结果，我们将使用来自墨西哥城ELEMENT研究的人群，对母亲和婴儿进行类似的评估。虽然已经提出了一些理论模型来解释社会条件如何“进入身体”来影响健康，但社会心理压力模型越来越多地被采用。这项研究可能会开始告知这是如何发生在最基本的水平。