The Timing of In Utero Caffeine Exposure Influences the Morphological, Functional, and Trans‐generational Effects on Adult Hearts

Abstract

It is recognized that the disruption of the intrauterine environment by nutritional or chemical factors may influence the developing fetus, resulting in long‐term adverse effects in adulthood and subsequent generations. Previously, we demonstrated that in utero caffeine exposure in mice leads to altered cardiac function and morphology in adult offspring, which is accompanied by changes in DNA methylation and cardiac gene expression. We next hypothesized that the timing of in utero caffeine exposure influences which generation is affected, either the exposed embryo (F1) or subsequent generations (F2, exposed gametes, or F3 unexposed). To test this hypothesis, we treated pregnant CD‐1 dams with 20 mg/kg of caffeine daily from E6.5‐9.5, to target DNA re‐methylation in the embryo, or from E10.5‐13.5, to target DNA de‐methylation occurring during gametogenesis. In the F1 generation, early caffeine exposure from E6.5‐9.5 increased LV internal diameter (LVID) and volume, decreased LV posterior wall (LVPW) thickness and decreased % fractional shortening (FS) at 1 year of age, which is consistent with dilated cardiomyopathy. Adult cardiac gene expression was also affected including increased Myh7 expression. For late caffeine exposure from E10.5‐13.5, no effects on cardiac morphology or function were observed at either 12 weeks or 1 year in the F1 generation. However, in the late caffeine exposed F2 generation, we observed increased LVPW thickness, decreased LV volume and increased %FS, which is consistent with concentric cardiac hypertrophy.ConclusionIn utero caffeine exposure leads to changes in adult cardiac morphology and function. The timing of caffeine exposure not only influence which generation is affected but also the cardiac phenotype.