There is considerable evidence for induction of differential risk of noncommunicable diseases in humans by variation in the quality of the early life environment. Studies in animal models show that ...induction and stability of induced changes in the phenotype of the offspring involve altered epigenetic regulation by DNA methylation and covalent modifications of histones. These findings indicate that such epigenetic changes are highly gene specific and function at the level of individual CpG dinucleotides. Interventions using supplementation with folic acid or methyl donors during pregnancy, or folic acid after weaning, alter the phenotype and epigenotype induced by maternal dietary constraint during gestation. This suggests a possible means for reducing risk of induced noncommunicable disease, although the design and conduct of such interventions may require caution. The purpose of this review is to discuss recent advances in understanding the mechanism that underlies the early life origins of disease and to place these studies in a broader life-course context.
Traditionally it has been widely accepted that our genes together with adult lifestyle factors determine our risk of developing non-communicable diseases such as type 2 diabetes mellitus, ...cardiovascular disease and obesity in later life. However, there is now substantial evidence that the pre and early postnatal environment plays a key role in determining our susceptible to such diseases in later life. Moreover the mechanism by which the environment can alter long term disease risk may involve epigenetic processes. Epigenetic processes play a central role in regulating tissue specific gene expression and hence alterations in these processes can induce long-term changes in gene expression and metabolism which persist throughout the lifecourse. This review will focus on how nutritional cues in early life can alter the epigenome, producing different phenotypes and altered disease susceptibilities.
The rapid increase in the incidence of chronic non-communicable diseases over the past two decades cannot be explained solely by genetic and adult lifestyle factors. There is now considerable ...evidence that the fetal and early postnatal environment also strongly influences the risk of developing such diseases in later life. Human studies have shown that low birth weight is associated with an increased risk of CVD, type II diabetes, obesity and hypertension, although recent studies have shown that over-nutrition in early life can also increase susceptibility to future metabolic disease. These findings have been replicated in a variety of animal models, which have shown that both maternal under- and over-nutrition can induce persistent changes in gene expression and metabolism within the offspring. The mechanism by which the maternal nutritional environment induces such changes is beginning to be understood and involves the altered epigenetic regulation of specific genes. The demonstration of a role for altered epigenetic regulation of genes in the developmental induction of chronic diseases raises the possibility that nutritional or pharmaceutical interventions may be used to modify long-term cardio-metabolic disease risk and combat this rapid rise in chronic non-communicable diseases.
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.
Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid ...supplementation on the epigenetic regulation of genes in adult humans.
We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5' regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts.
These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function.
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 PPARalpha 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 PPARalpha and GR promoter methylation was significantly (P<0.05) lower in the PRD group in the F1 (PPARalpha 8 %, GR 10 %) and F2 (PPARalpha 11 %, GR 8 %) generations. There were trends (P<0.1) towards a higher expression of PPARalpha, 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.
Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a ...mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.
We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.
Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.
ISRCTN89971375.
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.
Induction of altered phenotypes during development in response to environmental input involves epigenetic changes. Phenotypic traits can be passed between generations by a variety of mechanisms, ...including direct transmission of epigenetic states or by induction of epigenetic marks de novo in each generation. To distinguish between these possibilities we measured epigenetic marks over four generations in rats exposed to a sustained environmental challenge. Dietary energy was increased by 25% at conception in F0 female rats and maintained at this level to generation F3. F0 dams showed higher pregnancy weight gain, but lower weight gain and food intake during lactation than F1 and F2 dams. On gestational day 8, fasting plasma glucose concentration was higher and β-hydroxybutyrate lower in F0 and F1 dams than F2 dams. This was accompanied by decreased phosphoenolpyruvate carboxykinase (PEPCK) and increased PPARα and carnitine palmitoyl transferase-1 mRNA expression. PEPCK mRNA expression was inversely related to the methylation of specific CpG dinucleotides in its promoter. DNA methyltransferase (Dnmt) 3a2, but not Dnmt1 or Dnmt3b, expression increased and methylation of its promoter decreased from F1 to F3 generations. These data suggest that the regulation of energy metabolism during pregnancy and lactation within a generation is influenced by the maternal phenotype in the preceding generation and the environment during the current pregnancy. The transgenerational effects on phenotype were associated with altered DNA methylation of specific genes in a manner consistent with induction de novo of epigenetic marks in each generation.
Fatty acids and epigenetics Burdge, Graham C; Lillycrop, Karen A
Current opinion in clinical nutrition and metabolic care
17, Issue:
2
Journal Article
Peer reviewed
Open access
The purpose of this review is to assess the findings of recent studies on the effects of fatty acids on epigenetic process and the role of epigenetics in regulating fatty acid metabolism.
The DNA ...methylation status of the Fads2 promoter was increased in the liver of the offspring of mice fed an α-linolenic acid-enriched diet during pregnancy. In rats, increasing total maternal fat intake during pregnancy and lactation induced persistent hypermethylation of the Fads2 promoter in the liver and aortae of their offspring. However, increased fish oil intake in adult rats induced transient, reversible hypermethylation of Fads2. High-fat feeding in rodents also altered the levels of histone methylation in placentae and in adipose tissue. Dietary docosahexaenoic acid supplementation in pregnant women induced marginal changes in global DNA methylation in cord blood leukocytes. A high fat diet altered the DNA methylation status of specific genes in skeletal muscle in young men.
There are emerging findings that support the suggestion that fatty acids, in particular polyunsaturated fatty acids, can modify the epigenome. However, there is a need for rigorous investigations that assess directly the effect epigenetic modifications induced by fatty acids on gene function and metabolism.
PDF
