DNA methylation profiles of the 11-beta HSD2 promoter are related to childhood and lifetime trauma in pregnant women : project ACCESS

Background: Determining the range of environmental exposures which might affect the epigenome during critical periods of development is an active area of research. Prenatal maternal stress may have long-lasting programming effects on the physiological development of children mediated through altered activity of the maternal hypothalamic-pituitary-adrenocortical (HPA) axis. Maternal HPA functioning, in turn, may be altered by traumatic life experiences albeit the mechanisms underlying these effects are not fully elucidated. We examined the influence of childhood and lifetime traumatic stressors on gene specific DNA methylation profiles of the 11-beta hydroxysteroid dehyrogenase type 2 (11-beta HSD2) promoter region in 229 pregnant mothers enrolled in the Asthma Coalition on Community, Environment, and Social Stress (ACCESS) project, a prospective urban cohort designed to study the effects of early life stress on childhood asthma risk. Methods: Early life trauma history was collected using the Childhood Trauma Questionnaire (CTQ) and lifetime exposure was ascertained using the My Exposure to Violence (ETV) survey in approximately mid-pregnancy. Bisulfite-treated genomic DNA extracted from maternal peripheral blood mononuclear cells (pBMCs) was subjected to DNA methylation analysis by quantitative Pyrosequencing. Linear regression analyses predicting percent methylation in the 11-beta HSD2 promoter were adjusted for maternal age, race and education level, childhood and current socioeconomic status, gestational age at blood draw, prenatal smoking, and other current negative life events. For each trauma scale, those in the upper tertile (high trauma) were compared to those with lower scores. Results: Overall mean (SD) values for 11-beta HSD2 methylation was 90.4% (5.1%). Mean (SD) age was 26.4 (5.7) years. Among the women, 62% were Hispanic and 23.5% were African American, 67% had a high school education or lower, and 16.7% smoked during pregnancy. Higher levels of trauma on the CTQ (beta = 2.1, P = 0.005) and lifetime ETV scales (beta = 1.8, P = 0.07) independently predicted increased methylation. Conclusion: Maternal exposure to childhood trauma and cumulative lifetime violence (chronic stress) is associated with hypermethylation of the promoter region of 11-beta HSD2 in mother's leukocyte DNA. Hypermethylation has been associated with decreased expression of 11-beta HSD2 which modulates the intracellular access of glucocorticoids to their receptors. Conversely, up-regulation of of 11-beta HSD2 may protect against stress-induced elevated glucocorticoids. This, in turn, may have implications for maternal-fetal cortisol metabolism. Thus, epigenetic modulation of genes influencing prenatal HPA axis response may be one mechanism underlying prenatal programming effects of psychosocial stress on the next generation which warrants further study.