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


Principal Investigator: Rosalind J Wright
Abstract: 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.
Funding Period: 2012-09-01 - 2016-04-30
more information: NIH RePORT

Detail Information

Research Grants30

  1. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  2. Prenatal stress: the epigenetic basis of maternal and perinatal effects
    Benjamin Tycko; Fiscal Year: 2013
  3. Perinatal Stress and programming of childhood wheeze and lung function
    Rosalind J Wright; Fiscal Year: 2013
    ..Knowledge gained from the proposed research may inform new pathways linking stress to lung structure-function changes. ..
  4. EMA Assessment of Biobehavioral Processes in Human Pregnancy
    Pathik D Wadhwa; Fiscal Year: 2013
    ..Findings from our study also will inform the proposed psychobiological stress assessment protocol of the National Children's Study (NCS). ..
  5. Fetal exposure to maternal stress and inflammation: Effects on neurodevelopment
    Lauren M Ellman; Fiscal Year: 2013
    ..The present study has the potential to influence the development of early intervention and prevention strategies, as well as to identify early risk markers for subsequent difficulties in adolescence. ..
  6. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  7. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
    Pathik D Wadhwa; Fiscal Year: 2013
    ..abstract_text> ..