Caffeine induces both short‐term and long‐term effects on gene expression and DNA methylation in the mouse heart (542.3)

Abstract

Introduction: Evidence indicates that disruption of normal prenatal development influences an individual’s risk of developing cardiovascular disease as adults. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. One substance that fetuses are commonly exposed is caffeine, an adenosine receptor antagonist, with consumption during the first month of pregnancy being reported by 60% of women. Methods: Pregnant CD‐1 dams were injected with 20 mg/kg of caffeine once a day from E6.5‐E9.5. Hypothesis: Altered adenosine action in utero leads to adverse effects on adult heart function and morphology, and these effects are mediated by DNA methylation‐induced changes in cardiac gene expression. Results: Using an outbred strain of mouse, CD‐1, we demonstrated that in utero caffeine exposure induces increased wall thickness and increased left ventricular mass in adult hearts. When we examined gene expression in embryonic hearts following the same caffeine treatment, we demonstrated that enzymes responsible for DNA methylation and demethylation were affected. The DNA methylation genes DNA methyltransferase 1 and 3a were both down regulated and the Tet 1 enzyme which initiates DNA demethylation was up regulated following in utero caffeine exposure. These results are consistent with our observations that in utero caffeine exposure results in global hypomethylation in the adult heart. In addition, the cardiac structural genes Myh7, titan, and troponin I1 had altered gene expression. Conclusion: Caffeine affects the expression level of genes that control DNA methylation in utero, and caffeine leads to altered gene expression and cardiac morphology in adulthood.Grant Funding Source: R01 HD058086