title: Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring.
abstract: Environmental constraints during early life result in phenotypic changes that can be associated with increased disease risk in later life. This suggests persistent alteration of gene transcription. DNA methylation, which is largely established in utero, provides a causal mechanism by which unbalanced prenatal nutrition results in such altered gene expression. We investigated the effect of unbalanced maternal nutrition on the methylation status and expression of the glucocorticoid receptor (GR) and peroxisomal proliferator-activated receptor (PPAR) genes in rat offspring after weaning. Dams were fed a control protein (C; 180 g/kg protein plus 1 mg/kg folic acid), restricted protein (R; 90 g/kg casein plus 1 mg/kg folic acid), or restricted protein plus 5 mg/kg folic acid (RF) diet throughout pregnancy. Pups were killed 6 d after weaning (n = 10 per group). Gene methylation was determined by methylation-sensitive PCR and mRNA expression by semiquantitative RT-PCR. PPARalpha gene methylation was 20.6% lower (P < 0.001) and expression 10.5-fold higher in R compared with C pups. GR gene methylation was 22.8% lower (P < 0.05) and expression 200% higher (P < 0.01) in R pups than in C pups. The RF diet prevented these changes. PPARgamma methylation status and expression did not differ among the groups. Acyl-CoA oxidase expression followed that of PPARalpha. These results show that unbalanced prenatal nutrition induces persistent, gene-specific epigenetic changes that alter mRNA expression. Epigenetic regulation of gene transcription provides a strong candidate mechanism for fetal programming.
authors.affiliation: Development and Cell Biology, University of Southampton, UK.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Lillycrop
authors.forename: Emma S
authors.initials: ES
authors.lastname: Phillips
authors.forename: Alan A
authors.initials: AA
authors.lastname: Jackson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hanson
authors.forename: Graham C
authors.initials: GC
authors.lastname: Burdge
mesh_terms: D042962:Acyl-CoA Oxidase / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D019175:DNA Methylation; D018753:Diet, Protein-Restricted; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D047493:PPAR alpha / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000235:genetics
chemical_list: D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D005492:Folic Acid; D042962:Acyl-CoA Oxidase