Maternal diet as a modifier of offspring epigenetics

There has been a substantial body of evidence, which has shown that genetic variation is an important determinant of disease risk. However, there is now increasing evidence that alterations in epigenetic processes also play a role in determining susceptibility to disease. Epigenetic processes, which include DNA methylation, histone modifications and non-coding RNAs play a central role in regulating gene expression, determining when and where a gene is expressed as well as the level of gene expression. The epigenome is highly sensitive to a variety of environmental factors, especially in early life. One factor that has been shown consistently to alter the epigenome is maternal diet. This review will focus on how maternal diet can modify the epigenome of the offspring, producing different phenotypes and altered disease susceptibilities

The effect of dietary protein restriction in pregnant rats on the expression of DNA methyltransferases and methyl CpG binding protein 2 in the liver after weaning.

Induction of a modified metabolic phenotype in the offspring by feeding a protein-restricted (PR) diet during pregnancy in the rat involves DNA hypomethylation and altered covalent histone modifications leading to increased expression of specific genes (Lillycrop et al. 2005a,b). Hypomethylation of gene promoters may be achieved by impaired DNA methylation de novo, loss of CpG methylation during mitosis, or active demethylation. Histone modifications which modulate transcription involve binding of methyl CpG binding protein (MeCP)-2 to methylated DNA and recruitment of histone-modifying enzymes (Bird, 2002). We investigated in the offspring the effect of feeding a PR diet during pregnancy on the expression of hepatic DNA methyltransferase (DMNT) 1 which maintains CpG methylation, DNMT 3a and 3b which catalyse DNA methylation de novo and the DNA demethylase MBD2

Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life?

There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in man is associated with a graded risk of metabolic disease; fetal programming. It is likely that the induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of human subjects and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In the present review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life

Non-imprinted epigenetics in fetal and postnatal development and growth

Recent evidence demonstrates that the environment in early life can have important effects on fetal and postnatal growth, on development and on risk of developing common non-communicable diseases in later life. In animals, the environment during early life induces altered phenotypes in ways which are influenced or mediated by epigenetic mechanisms. The latter include DNA methylation, covalent modifications of histones and non-coding RNAs. Most is known about DNA methylation changes, which are gene specific, include effects on non-imprinted genes and function at the level of individual CpG dinucleotides to alter gene expression. Preliminary evidence from human studies suggests a similar important role for epigenetic processes. Tuning of phenotype by the developmental environment has adaptive value because it attempts to match an individual's responses to the environment predicted to be experienced later; hence, such processes have been selected during evolution as conferring fitness advantage. When the phenotype is mismatched, e.g. from inaccurate nutritional cues from the mother or placenta before birth, or from rapid environmental change through improved socioeconomic conditions, risk of non-communicable diseases increases. Evidence is accruing that endocrine or nutritional interventions during early postnatal life can reverse epigenetic and phenotypic changes induced, for example, by unbalanced maternal diet during pregnancy. Elucidation of epigenetic processes may enable early intervention strategies to improve early development and growth

Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator-activated receptors in the liver and adipose tissue of the offspring

The effect of protein consumption during pregnancy on peroxisomal proliferator-activated receptor (PPAR) expression and plasma lipid concentrations in the offspring were determined in the rat. Rats were fed isocaloric diets containing either 18% (w/w) (control) or 9% (w/w) casein throughout pregnancy, and chow during lactation. Maternal protein intake did not alter fetal hepatic PPAR? and ? expression at 20/21 days gestation (n = 5/group). Liver PPAR? expression was 69% greater (P < 0.0001) in the 9% group, whereas PPAR? was not altered, in the offspring 6 days after weaning (n = 5/group). Adipose PPAR? expression was 59% lower (P < 0.01) in the 9% group after weaning. This was accompanied by an increase (35%, P < 0.02) in plasma triacylglycerol and nonesterified fatty acid concentrations (55%, (P < 0.01) in the 9% group after weaning. These data show that maternal protein intake during pregnancy alters the regulation of PPAR expression, which represents a potential mechanism to explain impaired lipid homeostasis in the offspring

Dietary protein restriction in the pregnant rat induces altered epigenetic regulation of the glucocorticoid receptor and peroxisomal proliferator-activated receptor alpha in the heart of the offspring which is prevented by folic acid.

In healthy individuals, glucose and fatty acids are substrates for ATP generation in the heart. There is emerging evidence from patients with type 2 diabetes mellitus that preferential use of fatty acid b-oxidation for energy production may be linked to cardiomyopathy (Fink, 2004). PPARa activity is important for regulating fatty acid b-oxidation in the heart and is increased in hearts of rats with experimentally induced diabetes (Fink, 2004). Prenatal undernutrition is related inversely to risk of type 2 diabetes mellitus in man (Poole & Byrne, 2005) and insulin resistance in rats (Bertram & Hanson, 2001). We have shown that maternal dietary protein restriction induces persistent alterations to hepatic and carbohydrate metabolism in the offspring by altering the epigenetic regulation of PPARa and the glucocorticoid receptor(GR) (Lillycrop et al. 2005). Here we have tested the hypothesis that prenatal protein restriction  induces hypomethylation of the GR and PPARa promoters in the heart, and that this is prevented by supplementation of the protein-restricted (PR) diet with folic acid