|Several lines of evidence indicate that epigenetic modification may be a key unifying mechanism mediating risk associated with a perturbed intrauterine environment. First, disruption of physiologic responses and functional capacity as observed in multiple tissues of IUED or IUGR animals and humans, including muscle, adipose, pancreas, liver, and CNS may be related to histone modification and DNA methylation, thereby altering related gene expression .|
The preimplantation embryo is particularly sensitive to epigenetic modifications that might permanently alter the phenotype in the adult [105, 137]. For example, in the agouti mouse model, folate supplementation of the maternal diet at conception increases DNA methylation of the agouti gene and increases longevity of the offspring . Maternal protein restriction has been shown to alter the methylation status of the promoters of the glucocorticoid receptor , PPARα , and the angiotensin receptor  with parallel changes in gene expression. More recent studies have shown that histone modifications can also be influenced by the early environment. Alterations in histone modifications have also been implicated in mediating the effect of caloric restriction during the second half of pregnancy on the programmed reduction of GLUT4 expression in the offspring . In the case of the UPI rat model and the pancreatic tissue, Stoffers and colleagues have reported a progressive reduction in expression of Pdx1, a key transcription factor regulating pancreatic development and function . Pdx1 expression is reduced by 50% in UPI fetuses and by 80% in adult UPI offspring. Notably, these changes precede the onset of beta-cell dysfunction, suggesting a primary pathogenic role. Since the Pdx1 promoter is a target for epigenetic modification, as it contains a conserved CpG islands and is associated with high levels of histone acetylation. Interestingly, binding of both acetylated histone H3/H4 and the transcription factor USF1 was found abolished in UPI fetuses . While there was methylation at multiple CpGs in UPI adult offspring, no methylation was detected in UPI neonates, indicating that methylation was unlikely to explain Pdx1 repression early in life. Together, these data indicate that progressive silencing of gene expression is largely initiated by early epigenetic changes and is maintained thereafter even in the absence of further experimental insults during postnatal life. UPI also increases histone acetylation of the PPARγ coactivator PGC-1 and carnitine-palmitoyltransferase I (CPT1) promoters in newborn and young rats, and these changes are associated with increased PGC-1 and CPT1 mRNAs . Finally, there is now little doubt that epigenetic regulation of gene expression also occurs in humans as a response to early nutritional insult: a recent study has revealed that individuals who were exposed to famine in utero during the Dutch Hunger Winter had altered methylation of the Igf2 gene in white blood cells in adulthood .