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

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 F-1 generation by feeding a protein-restricted diet (PRD) during pregnancy involves the altered methylation of specific gene promoters. We therefore investigated whether the altered methylation of PPAR alpha and glucocorticoid receptor (GR) promoters was passed to the F-2 generation. Females rats (F-0) were fed a reference diet (180g/kg protein) or PRD (90g/kg protein) throughout gestation, and AIN-76A during lactation. The F-1 offspring were weaned onto AIN-76A. F-1 females were mated and fed AIN-76A throughout pregnancy and lactation. F-1 and F-2 males were killed on postnatal day 80. Hepatic PPARa and GR promoter methylation was significantly (P < 0.05) lower in the PRD group in the F, (PPARa 8%, GR 10%) and F-2 (PPARa 11%, GR 8%) generations. There were trends (PG 0.1) towards a higher expression of PPARa, GR, acyl-CoA oxidase and phosphoenolpyruvate carboxykinase (PEPCK) in the F-1 and F-2 males, although this was significant only for PEPCK. These data show for the first time that the altered methylation of gene promoters induced in the F-1 generation by maternal protein restriction during pregnancy is transmitted to the F-2 generation. This may represent a mechanism for the transmission of induced phenotypes between generations.