Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations

摘要

Epidemiological studies and experimental models show that maternal nutritional constraint during pregnancy alters the metabolic phenotype of the offspring and that this can be passed to subsequent generations. In the rat, induction of an altered metabolic phenotype in the liver of the F1 generation by feeding a protein-restricted diet (PRD) during pregnancy involves altered methylation of specific gene promoters. We therefore investigated whether altered methylation of peroxisomal proliferator-activated receptor (PPARα) and glucocorticoid receptor (GR) promoters is passed to the F2 generation. Females rats (F0) were fed a reference diet (RD, 18% protein) or PRD (9% protein) throughout gestation, and AIN76A during lactation. F1 offspring were weaned onto AIN76A. F1 females were mated and fed AIN76A throughout pregnancy and lactation. F1 and F2 males were killed on postnatal d 80. Hepatic PPARα and GR promoter methylation was significantly (P<0.05) lower in the PRD group in the F1 (PPARα 8%; GR 10%) and F2 (PPARα 11%; GR 8%) generations. There were trends (P<0.1) towards higher expression of PPARα, GR, acyl-CoA oxidase and phosphoenolpyruvate carboxykinase (PEPCK) in the F1 and F2 males, although this was only significant for PEPCK. These data show for the first time that altered methylation of gene promoters induced in the F1 generation by maternal protein-restriction during pregnancy is transmitted to the F2 generation. This may represent a mechanism for the transmission of induced phenotypes between generations.