Background: The fetal origins hypothesis postulated by Barker in the last century suggests that an adverse intrauterine environment induces changes that persist into adulthood. This intrauterine programming is not achieved by alterations in DNA sequence but by epigenetic mechanisms. We have investigated the role of epigenetics in hypercholesterolemia (HC), as well as in hyperglycemia (HG) models.
Methods: For the HC study we generated genetically identical heterozygous ApoE-deficient and LdLr-deficient progeny from mothers with a wild-type or a null-background. For the HG study we studied the effect of high glucose levels on neural crest cell contribution and applied antioxidant treatment to possibly reduce cardiac malformation damage in a chicken model. End-glycation product, VEGF and Smad expression were studied in a diabetic rat model with genetic susceptibility for cardiac malformations.
Results: In HC we showed that the maternal background was essential for development of profound atherosclerosis in the offspring. The combined information from both the ApoE and Ldlr-deficient offspring showed that HC was not the primary initiator. The inflammatory status of the ApoE-deficient mother seems to be very important. In the latter altered histone methylation was found in endothelial and smooth muscle cells of the affected offspring. In HG we showed that oxidative stress was involved in the development of congenital heart disease with predominance for outflow tract anomalies.
Conclusion: The studied models underscore the effect of in utero priming of the offspring on childhood and adult disease. Epigenetic factors such as altered methylation guide us towards further mechanistic research