Abstract
Each year millions of pregnant woman are exposed to caffeine, which acts to antagonize adenosine action. The long-term consequences of this exposure on the developing fetus are largely unknown, although in animal models we have found adverse effects on cardiac function. To assess if these effects are transmitted transgenerationally, we exposed pregnant mice to caffeine equivalent to 2–4 cups of coffee at two embryonic stages. Embryos (F1 generation) exposed to caffeine early from embryonic (E) day 6.5–9.5 developed a phenotype similar to dilated cardiomyopathy by 1 year of age. Embryos exposed to caffeine later (E10.5–13.5) were not affected. We next examined the F2 generation and F3 generation of mice exposed to caffeine from E10.5–13.5, as this coincides with germ cell development. These F2 generation adult mice developed a cardiac phenotype similar to hypertrophic cardiomyopathy. The F3 generation exhibited morphological changes in adult hearts, including increased mass. This report shows that in utero caffeine exposure has long-term effects into adulthood and that prenatal caffeine exposure can exert adverse transgenerational effects on adult cardiac function.
Highlights
It is well recognized that disruption of the intrauterine environment by nutritional or chemical factors may influence the fetus, resulting in long-term adverse effects after birth and into adulthood[1,2,3,4]
At 22 weeks after birth, F1 generation offspring of dams treated from E6.5–9.5 with caffeine had altered cardiac morphology, including increased interventricular septum (IVS) thickness during both systole and diastole, and increased left ventricle (LV) mass compared to vehicle controls (Table 1)
At one year of age, F1 generation mice exposed to caffeine in utero from E6.5–9.5 showed altered cardiac morphology, as well as altered cardiac function that was characteristic of dilated cardiomyopathy
Summary
It is well recognized that disruption of the intrauterine environment by nutritional or chemical factors may influence the fetus, resulting in long-term adverse effects after birth and into adulthood[1,2,3,4]. The notion that prenatal caffeine exposure is associated with low birth weight and other adverse effects is not accepted by all[14,25], it is concerning enough that Nordic countries, the United Kingdoms, and the United States recommend that pregnant women limit their caffeine intake to less than 200 mg per day[26,27]. Maternal exposure to caffeine is associated with altered brain development and behavioral changes in neonatal and adult offspring[28,29]. Caffeine has long-lasting effects as well including reduced birth weight and growth in neonates and adverse behavior at 18 months[33,34,35]. Alterations in DNA methylation patterns are recognized to transduce in utero environmental stress into an increased risk for adult www.nature.com/scientificreports/
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