Full Papers

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

Graham C. Burdgea1 c1, Jo Slater-Jefferiesa1, Christopher Torrensa1, Emma S. Phillipsa2, Mark A. Hansona1 and Karen A. Lillycropa2

a1 Developmental Origins of Health and Disease Division, University of Southampton, Southampton, UK

a2 Development and Cell Biology, University of Southampton, Southampton, UK


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 the altered methylation of specific gene promoters. We therefore investigated whether the altered methylation of PPARα and glucocorticoid receptor (GR) promoters was passed to the F2 generation. Females rats (F0) were fed a reference diet (180 g/kg protein) or PRD (90 g/kg protein) throughout gestation, and AIN-76A during lactation. The F1 offspring were weaned onto AIN-76A. F1 females were mated and fed AIN-76A throughout pregnancy and lactation. F1 and F2 males were killed on postnatal day 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 a higher expression of PPARα, GR, acyl-CoA oxidase and phosphoenolpyruvate carboxykinase (PEPCK) in the F1 and F2 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 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.

(Received June 12 2006)

(Revised September 18 2006)

(Accepted October 09 2006)


c1 *Corresponding author: Dr G. C. Burdge, fax +44 (0)2380 594379, email g.c.burdge@soton.ac.uk


Abbreviations: AOX, acyl-CoA oxidase; GR, glucocorticoid receptor; PEPCK, phosphoenolpyruvate carboxykinase; PRD, protein-restricted diet; RD, reference diet