Longitudinal effects of developmental bisphenol A, variable diet, and physical activity on age-related methylation in blood

Research indicates that environmental factors can alter DNA methylation, but the specific effects of environmental exposures on epigenetic aging remain unclear. Here, using a mouse model of human-relevant exposures, we tested the hypothesis that early-life exposure to bisphenol A (BPA), variable diet, and/or changes in physical activity would modify rates of age-related methylation at several target regions, as measured from longitudinal blood samples (2, 4, and 10 months old). DNA methylation was quantified at two repetitive elements (LINE-1, IAP), two imprinted genes (Igf2, H19), and one non-imprinted gene (Esr1) in isogenic mice developmentally exposed to Control, Control + BPA (50 µg/kg diet), Western high-fat diet (WHFD), or Western + BPA diets. In blood samples, Esr1 DNA methylation increased significantly with age, but no other investigated loci showed significant age-related methylation. LINE-1 and IAP both showed significant negative environmental deflection by WHFD exposure (P < 0.05). Esr1also showed significant negative environmental deflection by WHFD exposure in female mice (P = 0.02), but not male mice. Physical activity had a non-significant positive effect on age-related Esr1 methylation in female blood, suggesting that it may partially abrogate the effects of WHFD on the aging epigenome. These results suggest that developmental nutritional exposures can modify age-related DNA methylation patterns at a gene related to growth and development. As such, environmental deflection of the aging epigenome may help to explain the growing prevalence of chronic diseases in human populations.