Cambridge University Press, British Journal of Nutrition, 6(97), p. 1064-1073, 2007
DOI: 10.1017/s000711450769196x
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Prenatal nutritional constraint induces an altered metabolic phenotype in the offspring which in humans confers an increased risk of non-communicable disease. Feeding a protein-restricted (PR) diet to pregnant rats causes hypomethylation of specific gene promoters in the offspring and alters the phenotype. We investigated how altered epigenetic regulation of the hepatic glucocorticoid receptor (GR) 110promoter is induced in the offspring. Rats were fed a control (180 g casein/kg) or a PR (90 g casein/kg) diet throughout pregnancy, and chow during lactation. Offspring were killed at postnatal day 34 (n5 per maternal dietary group). Methylation-sensitive PCR showed that GR110promoter methylation was 33 % lower (P < 0·001) and GR expression 84 % higher (P < 0·05) in the PR offspring. Reverse transcription–PCR showed that DNA methyltransferase-1 (Dnmt1) expression was 17 % lower (P < 0·05) in PR offspring, while Dnmt3a/b and methyl binding domain protein-2 expression was not altered. Thus hypomethylation of the GR110promoter may result from lower capacity to methylate hemimethylated DNA during mitosis. Histone modifications which facilitate transcription were increased at the GR110promoter (147–921 %,P < 0·001), while those that suppress methylation were decreased (54 %,P < 0·01) or similar to controls. In human umbilical cord (n15), there was a 2-fold difference between the highest and lowest level of GR1-CTotalpromoter methylation. Dnmt1, but not Dnmt3a, expression predicted 49 % (P = 0·003) of the variation in GR1-CTotalpromoter methylation. These findings suggest that induction in the offspring of altered epigenetic regulation of the hepatic GR110promoter, and hence metabolic phenotype, may be due to reduced Dnmt1 expression.