Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition

Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age-related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers' nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age-matched young controls and aged (20-month-old) animals. HELP-tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9weeks old with more significant changes at 6months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease.