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188 Environ Health Prev Med (2013) 18:185–197effects on development is often referred to as ‘metabolicprogramming’ [42].The stress response may be involved in the pathogenesisof DOHaD via the regulation of the hypothalamic–pituitary–adrenal (HPA) axis, which has potent effects onmetabolism and vasculature [43, 44]. Changes in the HPAaxis have been proposed as a mechanism behind theepidemiological link between LBW and later increasedblood pressure [45]. Offspring of rat dams given dexamethasoneduring pregnancy have reduced birth weightand increased blood pressure and glucose intolerance inadulthood [46, 47]. Intrauterine stress is associated withinsulin resistance and accompanying dysregulation of theHPA axis, with chronically excessive adrenal glucocorticoidsecretion and increased stress responses [48].Mechanistic analysis has shown that intrauterine glucocorticoidexposure leads to reduced numbers of glucocorticoidreceptors in the hypothalamus, resulting inimpaired negative feedback and hence long-term upregulationof the HPA axis after birth [49]. This, in turn, maycontribute to increased blood pressure and glucose intolerance.In humans, exposure to antenatal betamethasonecaused signs of insulin resistance in adult offspring at30 years of age [50]. Thus, increased maternal corticosteroidlevels as a result of stress induced by reducednutrient availability induce hypertension in the offspring[51]. A recent study reported that maternal iron restriction,independent of maternal macronutrient or caloricintake, also works as a fetal stressor that programs metabolicand circulatory functions in the offspring [52].Animal studies are used to clarify the underlyingmechanisms of clinical observations in more detail. Fetalnutrition is a key regulator of fetal growth and thus anobvious candidate as an influence on programming [53]. Infact, rats living in a postnatal obesogenic environment havevery different physiological responses depending on whetherthey were born to undernourished or well-fed mothers,with the former becoming more obese, more hypertensive,and more hyperphagic than the latter [54]. Imbalance ofprotein and carbohydrate intake during pregnancy has beenassociated with reduced birth weight and increased bloodpressure in the offspring [55]. Many studies have shownthat prenatal protein restriction results in LBW and programshypertension in experimental animals [56–58].Embryos collected from mothers fed a low-protein diethave reduced cell numbers [59]. In particular, a strongcorrelation has been found between nephron number andbirth weight [60], and a reduction in nephron number isassociated with increased blood pressure [61]. Exposure ofrats to a low-protein diet in utero also decreases b-cellproliferation, islet size, and islet vascularization [62].Subsequent accelerated growth leads to an excessive metabolicdemand on this limited cell mass.Transcriptome-wide analysis using the AffymetrixMouse 430A_2.0 array (Affymetrix, Santa Clara, CA)showed that feeding mice a protein-restricted diet betweengestational days 10.5 and 17.5 altered the expression of 235genes in the placenta [63]. In the adult male offspring ofdams fed a protein-restricted diet, 311 genes in the liverdiffered significantly from those in the offspring of controldams, as determined by the Agilent 014879 whole ratgenome array (Agilent Technologies, Santa Clara, CA)[64]. Thus, an altered maternal diet during pregnancyinduces persistent changes in the transcriptome. Whateverthe mechanisms, these events may occur in humans ifundernutrition in utero is followed by an abundant postnataldiet, such in small babies born into a food-richWestern society.Role of epigeneticsThe induction of altered phenotypes during development inresponse to environmental stimuli involves epigeneticchanges. Epigenetic regulation has been defined as ‘‘heritablechanges in gene function that occur without changesin the nucleotide sequence’’ [65]. Epigenetic factorsinclude DNA methylations, histone modifications, andmicroRNAs. Epigenetic changes, in particular in DNAmethylation, provide a ‘memory’ of developmental plasticresponses to the early environment and are central to thegeneration of phenotypes and their stability throughout thelife course. Methylation at the 5 0 position of cytosine inDNA within a CpG dinucleotide (the p denotes the interveningphosphate group) is a common modification inmammalian genomes and constitutes a stable epigeneticmark that is transmitted through DNA replication and celldivision [66]. CpG dinucleotides are not randomly distributedthroughout the genome but are clustered at the 5 0ends of genes/promoters in regions known as CpG islands.Hypermethylation of these CpG islands is generally associatedwith transcriptional repression, while hypomethylationof CpG islands is generally associated withtranscriptional activation.Data from animal models suggest that epigenetic processesare an important link between the early life environmentand altered metabolism and body composition inthe adult offspring [67, 68]. A growing body of literaturehas reported a role for epigenetic factors in the complexinterplay between genes and the environment [4, 69–71].Epigenetic changes may explain how an altered maternaldiet during pregnancy, such as a protein restricted diet,induces persistent changes in the transcriptome.Environmental developmental influences, such as thematernal diet or chemical exposure, can affect the offspringphenotype via epigenetic effects [72, 73]. A diet that is poor123
Environ Health Prev Med (2013) 18:185–197 189or enriched in methyl donors and cofactors of DNA methylation,especially during fetal growth and development,may influence the epigenotype. For example, a methyl-richmaternal diet during gestation was found to alter the bodycomposition of the offspring in agouti mice, which wasaccompanied by epigenetic changes in metabolic controlgenes [74]. Thus, environmentally induced epigeneticmodifications alter gene expression and may increase theoffspring’s susceptibility for later disease [75, 76].It has been shown in rodent models that unbalancedmaternal diets during pregnancy induce changes in DNAmethylation and covalent histone modifications in the 5 0regulatory regions of specific non-imprinted genes,affecting the offspring’s later body composition and metabolicphenotype [77, 78]. For example, the offspring of ratdams fed a protein-restricted diet had lower levels of CpGmethylation and greater expression of the peroxisomeproliferators-activated receptor (PPAR) a and glucocorticoidreceptor (GR) genes in the liver than control animals[77]. Changes in the epigenetic regulation of these genesmay result in alterations in the activity of pathways controlledby their target genes, such as phosphoenolpyruvatecarboxykinase and acyl-CoA oxidase, which subsequentlyaffects lipid and carbohydrate metabolism. Hypomethylationof the hepatic PPARa and GR promoters has beenreported in both F1 and F2 offspring of F0 rats fed a protein-restricteddiet during pregnancy without furthernutritional challenge to the F1 generation, indicating thatchanges in the epigenome that occur during developmentmay be passed on to subsequent generations [68].Intrauterine growth restriction has been associated withprogressive epigenetic silencing of Pdx1, a pancreatic andduodenal homeobox 1 transcription factor critical for b-celldevelopment, resulting in impaired b-cell function andT2D in the adult offspring in rats [79]. Lack of methylationof the retrotransposon with a methylation-sensitive promoterwas associated with subsequent offspring obesity inmice [80]. In contrast, supplementation of the diets ofpregnant animals with methyl donors, such as folic acid,vitamin B12, choline, or betaine, increased DNA methylationof specific genes in the offspring [74, 81–83].Overall, these results show that dietary modifications caninduce altered phenotypes through epigenetic changes inspecific genes and that these changes in phenotype can bemodulated by nutritional interventions during pregnancy.As yet there are limited published human data linkingmaternal nutrition to epigenetic changes in the offspring.Adults who were exposed to famine in utero showedaltered DNA methylation in the promoters of severalimprinted and non-imprinted genes in white blood cells.Two studies on the Dutch hunger winter families reportedthe effects of prenatal undernutrition on promoter methylation[84, 85]. Individuals with periconceptual exposure tofamine had reduced DNA methylation of the imprintedinsulin-like growth factor-2 (IGF2) gene, a key factor inhuman growth and development, as compared with theirunexposed, same-sex siblings at 59 years of age [84]. Inaddition, individuals from Dutch hunger winter familiesalso had lower DNA methylation of the imprinted INS-IGF2 (INSIGF) gene, but increased DNA methylation ofthe guanine nucleotide-binding protein (GNASAS), maternallyexpressed 3 (MEG3), interleukin-10 (IL10), ATPbindingcassette A1 (ABCA1), and leptin (LEP) genes inparallel with impaired glucose tolerance compared withtheir unexposed same-sex siblings [85]. A recent studyreported that higher methylation of retinoid X receptor-achr9 was associated with lower maternal carbohydrateintake in early pregnancy, which is also associated withhigher neonatal adiposity [53]. Thus, it is clear that fetalstress can affect the methylation status of several subsets ofgenes, supporting the hypothesis that associations betweenearly developmental conditions and health outcomes laterin life may be mediated by changes in the epigeneticinformation. However, the differences in methylation statusof these genes between the exposed and unexposedindividuals were relatively small, although statisticallysignificant. Further studies with clear end points are neededto determine whether measurement of epigenetic marks inearly life can be used as biomarkers to identify individualswho have experienced environmental perturbations indevelopment and thus who are more likely to developobesity and metabolic disease in later adulthood. It iscrucial to identify such epigenetic marks that are predictiveof a later phenotype so that they can be used as relevantbiomarkers for disease prevention.Role of chemicalsBecause the obesity epidemic coincided with the rapidincrease in the use of industrial chemicals, the hypothesisthat exposure to chemicals, combined with genetic predispositionand consumption of a high-calorie diet, may bea major contributor to the obesity epidemic was proposednearly 10 years ago [86, 87]. Since then, a number ofstudies have specifically addressed the effects of environmentalchemical exposure on weight gain. Chemicals thataffect human fetal development are generally calledendocrine-disrupting chemicals (EDCs). EDCs are compoundsthat act upon the body’s hormonal systems andinclude industrial contaminants, plastics, pesticides, andother compounds [88]. EDC contamination is a globalproblem. Bisphenol A (BPA), the prototypical EDC, isproduced in large quantities for use in the production ofpolycarbonate and epoxy resins. However, when used infood and drink containers, it can ‘leach’ into the contents,123
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