Maternal distress, DNA methylation, and fetal programming of stress physiology in Brazilian mother-infant pairs

Objectives:Maternal prenatal psychosocial stress is associated with adverse hypothalamic-pituitary-adrenal axis function among infants. While the biological mechanisms influencing this process remain unknown, altered DNA methylation is considered to be one potential mechanism. We investigated associations between maternal prenatal psychological distress, infant salivary DNA methylation and stress physiology at 12 months. Methods: Mother’s distress was measured via depression and anxiety in early and late pregnancy in a cohort of 80 pregnant adolescents. Maternal hair cortisol was collected during pregnancy. Saliva samples were collected from infants at 12 months to quantify DNA methylation of three stress-related genes (FKBP5, NR3C1, OXTR) (n=62) and diurnal cortisol (n=29). Multivariable linear regression was used to test for associations between prenatal psychological distress, and infant DNA methylation and cortisol. Results: Hair cortisol concentrations in late pregnancy were negatively associated with two sites of FKBP5 (Site 1: B=-22.33, p=0.003; Site 2: B=-15.60, p=0.012). Infants of mothers with elevated anxiety symptoms in late pregnancy had lower levels of OXTR2 CpG2 methylation (B=-2.17, p=0.03) and higher evening salivary cortisol (B=0.41, p=0.03). Furthermore, OXTR2 methylation was inversely associated with evening cortisol (B=-.14, p-value≤0.001). Discussion: Our results are, to our knowledge, the first evidence that methylation of the oxytocin receptor may contribute to the regulation of hypothalamic-pituitary-adrenal axis during infancy