Not surprisingly, maternal nutrition alone or in combination with other prenatal determinants has been identified as a likely factor involved in the programming of offspring disease risk (55
). Recent epidemiological studies from the Dutch Hunger Winter and the 1959 to 1961 Chinese famines have provided convincing evidence that prenatal undernutrition increases the risk of schizophrenia twofold in adult life (56
). A variety of scenarios may explain these outcomes, including epigenetic programming effects related to levels of nutrients and methyl donors such as choline or folic acid during development (58
). Studies have begun to address the issue of epigenetic programming in schizophrenia risk by examining archived prenatal serum specimens for prospective biomarkers such as nutrient deficiency that might predict disease susceptibility. Examination of gene methylation changes associated with prenatal nutrition has revealed that individuals prenatally exposed to famine during the Dutch Hunger Winter showed reduced DNA methylation of the imprinted insulin-like growth factor 2 gene 6 decades later compared with unexposed same-sex siblings (60
). This outcome was specific to a periconceptional exposure supporting the conclusion that very early development is a critical time point in programming of epigenetic marks that may determine disease risk.
Mechanistic studies using a variety of animal models have dissected the link between the perinatal nutritional state and the offspring’s metabolic phenotype. As the organization of neural circuits controlling energy balance take shape during perinatal life, considerable attention has focused on the hypothalamus. The adipocyte hormone leptin plays a vital role in directing development of hypothalamic projections from the arcuate nucleus. Moreover, secretion of leptin during perinatal life changes in response to the nutritional environment and thus is poised to signal the developing brain regarding maternal overnutrition or undernutrition via distinct actions on two functionally divergent neuronal populations, the anorexigenic pro-opiomelanocortin and orexigenic neuropeptide Y neurons (61
). Targets of these neurons, such as the paraventricular nucleus and lateral hypothalamus, contain several cell types that exert widespread regulatory actions on energy balance and are likely impacted by numerous hormonal and neurotrophic factors yet to be defined. Such studies have perhaps identified specific modes of neurodevelopmental programming whereby the wiring of the hypothalamus is determined through endocrine signals (62
Equally intriguing is the possibility that perinatal nutritional cues influence growth, independent of adiposity, through central mechanisms that influence body length or height via epigenetic modifications of specific genes during early development (63
). Maternal exposure to a high-fat diet in mice results in both significant body length increases and reduced insulin sensitivity that persist across at least two generations. The acquisition of this phenotype in the second generation is not attributable to altered intrauterine conditions or maternal feeding behavior, as both maternal and paternal lineages pass on the effect to the second generation, supporting a germline-based epigenetic manner of inheritance. Similarly, a maternal low-protein diet affects offspring growth and food intake and recently was shown to disrupt the expression of dopamine-related molecules within the mesocorticolimbic circuitry and a number of dopamine-dependent reward-related behaviors (64
). Epigenetic modification (DNA hypomethylation) and subsequent effects on target genes (overexpression) are potential mechanisms linking suboptimal prenatal environment and adverse behavioral outcome.
Epigenetic mechanisms that exert lasting effects on gene expression and can be heritable are a particularly intriguing target when examining links between the perinatal nutritional environment and offspring metabolic phenotype. For example, foods high in choline cause marked changes in DNA methylation, which, in turn, alter long-term gene expression. Choline deficiency induced during gestation produced alterations in histone methylation and subsequent changes in gene expression in mice (66
). Pregnant dams fed choline-deficient diets during late gestation produced offspring with diminished progenitor cell proliferation and increased fetal hippocampus apoptosis, altered hippocampal angiogenesis, insensitivity to long-term potentiation as adults, and decremented visual-spatial and auditory memory. These changes in fetal brain development appeared to be mediated by epigenetic alterations such as maternal dietary choline-modulated DNA and histone methylation in the fetal hippocampus. Similarly, studies using changes in mouse coat color as a marker of dietary and nutrient influence on epigenetic regulation of the agouti locus document how relatively minor methylation changes can have a profound impact on gene expression (67
Further mechanistic examination of maternal nutritional state effects on programming of offspring health has been modeled in paradigms including placental insufficiency and hypoxia. Using uterine artery ligation to model intrauterine growth retardation and examine offspring diabetes development, studies have highlighted specific alterations in histone acetylation, decreasing the expression of genes including pancreatic duodenal homeobox 1, a growth factor critical in pancreatic development (68
). Recent observations suggesting that hormone receptor signaling pathways and genes that control expression of neurotrophic factors can be epigenetically regulated point to a promising avenue of future research.