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.

Public Health Relevance

Starting in utero, key homeostatic systems (HPA axis, ANS functioning), are vulnerable to stress-induced programming. Given evidence for the role of these systems in a wide range of somatic and mental health disorders, this has significant implications for lifetime disease risk in these children. Findings of this study may have broad applicability to understanding the links between adverse social conditions in early life and future chronic disease risk.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-PSE-B (50))
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Bosquet Enlow, Michelle; Bollati, Valentina; Sideridis, Georgios et al. (2018) Sex differences in effects of maternal risk and protective factors in childhood and pregnancy on newborn telomere length. Psychoneuroendocrinology 95:74-85
De Carli, Margherita M; Baccarelli, Andrea A; Trevisi, Letizia et al. (2017) Epigenome-wide cross-tissue predictive modeling and comparison of cord blood and placental methylation in a birth cohort. Epigenomics 9:231-240
Brunst, Kelly J; Sanchez Guerra, Marco; Gennings, Chris et al. (2017) Maternal Lifetime Stress and Prenatal Psychological Functioning and Decreased Placental Mitochondrial DNA Copy Number in the PRISM Study. Am J Epidemiol 186:1227-1236
Brunst, Kelly J; Kannan, Srimathi; Ni, Yu-Ming et al. (2016) Validation of a Food Frequency Questionnaire for Estimating Micronutrient Intakes in an Urban US Sample of Multi-Ethnic Pregnant Women. Matern Child Health J 20:250-60
Wilson, Sandra R; Rand, Cynthia S; Cabana, Michael D et al. (2012) Asthma outcomes: quality of life. J Allergy Clin Immunol 129:S88-123