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Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life. The long-term effect of prenatal nutrition on gene regulation is largely unknown. Here the authors identify differentially methylated regions in whole blood from individuals exposed to famine early after conception, and show that these epigenetic changes may have adverse metabolic consequences later in life.

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) 110 promoter 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 (n 5 per maternal dietary group). Methylation-sensitive PCR showed that GR110 promoter 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 GR110 promoter may result from lower capacity to methylate hemimethylated DNA during mitosis. Histone modifications which facilitate transcription were increased at the GR110 promoter (147–921 %, P < 0·001), while those that suppress methylation were decreased (54 %, P < 0·01) or similar to controls. In human umbilical cord (n 15), there was a 2-fold difference between the highest and lowest level of GR1-CTotal promoter methylation. Dnmt1, but not Dnmt3a, expression predicted 49 % (P = 0·003) of the variation in GR1-CTotal promoter methylation. These findings suggest that induction in the offspring of altered epigenetic regulation of the hepatic GR110 promoter, and hence metabolic phenotype, may be due to reduced Dnmt1 expression.

Background Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring. Results We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that “leptin reversal” is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring. Conclusions We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This “calibration model” for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.

Fetal malnutrition is an early-life inducer of dyslipidemia and glucose intolerance. The aim of this study was to examine whether maternal azuki bean (Vigna angularis) polyphenol (AP) intake during lactation affects the adenosine monophosphate–activated protein kinase (AMPK) pathway and lipid metabolism in offspring exposed to fetal malnutrition. Pregnant Wistar rats were divided into three groups: a control diet offered during gestation and lactation (CC), a low-protein diet during gestation and a control diet during lactation (LPC); and a low-protein diet during gestation and a 1.0% AP-containing control diet during lactation (LPAP). Male pups were randomly selected for the study; half the pups were sacrificed at 3 wk of age and the other half were fed a standard diet and sacrificed at 23 wk. Hepatic triacylglycerol levels, phosphorylation levels of AMPK and acetyl-coenzyme A carboxylase (ACC), and mRNA levels of sterol regulatory element-binding protein-1c (SREBP-1c) were evaluated. Significant decreases in body weights and hepatic triacylglycerol levels were found in the LPAP compared with the LPC group. Plasma adiponectin levels in the LPAP group were higher than those in the LPC group. AMPK phosphorylation was upregulated in the livers and skeletal muscles in young and adult LPAP compared with LPC rats. ACC phosphorylation was upregulated in skeletal muscles of LPAP rats. SREBP-1c mRNA expression was decreased in the livers of LPAP rats. Our results suggest that maternal AP intake during lactation upregulates AMPK phosphorylation not only in young but also in adult offspring exposed to fetal malnutrition and may lead to decreased hepatic lipid accumulation by ACC phosphorylation and downregulation of SREBP-1c expression.

Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring.

Summary Specific, often unbalanced diets are used to circumvent the metabolic defects of patients with monogenic inborn errors of metabolism. Human epidemiological studies and appropriately designed dietary interventions in animal models have provided considerable evidence to suggest that nutritional imbalance and metabolic disturbances, during critical time windows of developmental programming, may have a persistent effect on the health of the child and later in adulthood. Thus patients with monogenic inborn errors of metabolism may also suffer additional types of alterations due to the lack or excess of key nutrients. Interactions of nutrients with the epigenetic machinery lead to epigenetic changes associated with chromatin remodelling and regulation of gene expression that underlie the developmental programming of pathological consequences in adulthood. Today, with the explosion of new technologies, we can explore on a large scale the effects of nutrients on the level of expression of thousands of expressed genes (nutritional genomics and epigenomics), the corresponding protein products and their posttranslationally modified derivatives (proteomics), and the host of metabolites (metabolomics) generated from endogenous metabolic processes or exogenous dietary nutrients and can establish the relationship between these biological entities and diet, health or disease. The combination of these various lines of research on epigenetic programming processes should highlight new strategies for the prevention and treatment of inborn errors of metabolism.

Fetal alcohol spectrum disorder (FASD) encompasses the range of deleterious outcomes of prenatal alcohol exposure (PAE) in the affected offspring, including developmental delay, intellectual disability, attention deficits, and conduct disorders. Several factors contribute to the risk for and severity of FASD, including the timing, dose, and duration of PAE and maternal factors such as age and nutrition. Although poorly understood, genetic factors also contribute to the expression of FASD, with studies in both humans and animal models revealing genetic influences on susceptibility. In this article, we review the literature related to the genetics of FASD in humans, including twin studies, candidate gene studies in different populations, and genetic testing identifying copy number variants. Overall, these studies suggest different genetic factors, both in the mother and in the offspring, influence the phenotypic outcomes of PAE. While further work is needed, understanding how genetic factors influence FASD will provide insight into the mechanisms contributing to alcohol teratogenicity and FASD risk and ultimately may lead to means for early detection and intervention.

If sufficient nutrition is not obtained during pregnancy, the fetus changes its endocrine system and metabolism to protect the brain, resulting in a loss of body size. The detailed mechanisms that determine the success or failure of growth catch-up are still unknown. Therefore, we investigated the mechanism by which catch-up growth failure occurs. The body weights of rat pups at birth from dams whose calorie intake during pregnancy was reduced by 40% were significantly lower than those of controls, and some offspring failed to catch up. Short-body-length and low-bodyweight rats showed blood IGF-1 levels and mRNA expression levels of IGF-1 and growth hormone receptor (GHR) in the liver that were lower than those in controls. The next generation offspring from low-bodyweight non-catch-up (LBW-NCG) rats had high expression of miR-322 and low expression of GHR and IGF-1. The expression of miR-322 showed a significant negative correlation with GHR expression and body length, and overexpression of miR-322 suppressed GHR expression. We found that insufficient intake of calories during pregnancy causes catch-up growth failure due to increased expression of miR-322 and decreased expression of GHR in the livers of offspring, and this effect is inherited by the next generation.

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.

Epigenetic mechanisms are emerging as mediators linking early environmental exposures during pregnancy with programmed changes in gene expression that alter offspring growth and development. There is irrefutable evidence from human and animal studies that nutrient and environmental agent exposures (for example, endocrine disruptors) during pregnancy may affect fetal/newborn development resulting in offspring obesity and obesity-associated metabolic abnormalities (metabolic syndrome). This concept of ‘gestational programming’ is associated with alterations to the epigenome (nongenomic) rather than changes in the DNA sequence (genomic). Epigenetic alterations induced by suboptimal maternal nutrition/endocrine factors include DNA methylation, histone modifications, chromatin remodeling and/or regulatory feedback by microRNAs, all of which have the ability to modulate gene expression and promote the metabolic syndrome phenotype. Recent studies have shown tissue-specific transcriptome patterns and phenotypes not only in the exposed individual, but also in subsequent progeny. Notably, the transmission of gestational programming effects to subsequent generations occurs in the absence of continued adverse environmental exposures, thus propagating the cycle of obesity and metabolic syndrome. This phenomenon may be attributed to an extrinsic process resulting from the maternal phenotype and the associated nutrient alterations occurring within each pregnancy. In addition, epigenetic inheritance may occur through somatic cells or through the germ line involving both maternal and paternal lineages. Since epigenetic gene modifications may be reversible, understanding how epigenetic mechanisms contribute to transgenerational transmission of obesity and metabolic dysfunction is crucial for the development of novel early detection and prevention strategies for programmed metabolic syndrome. In this review we discuss the evidence in human and animal studies for the role of epigenomic mechanisms in the transgenerational transmission of programmed obesity and metabolic syndrome.