Epigenetics is an emergent field in public health: the increasing number and statistical strength of long-term studies, coupled with recent advances in bioinformatic technologies, strongly motivates consideration of the epigenetic realm as inseparable from public health goals and initiatives. Current work suggests possible relationships between nutrition and epigenetic modification, particularly in the case of developing neonates.
A better understanding of the epigenetic mechanisms involved in metabolism may inform our ability to affect health outcomes with early nutritional interventions, creating a new interface for disease prevention and public health intervention with the next generation. In both developed and developing economies, obesity stands out as a primary target for such intervention, not only as an epidemic in and of itself, but also in virtue of its close association with other non-communicable diseases (NCDs). Here we’ll consider a quick review of the literature on epigenetics, nutrition, and the developmental origins of metabolic health.
Developmental Origins of Health and Disease
While the mechanisms of epigenetic modification are complex, we understand that exposure to environmental insults can shape the epigenome, sometimes irreversibly so. This applies particularly to developing neonates, as epigenetics are strongly implicated in the DOHaD hypothesis (Developmental Origins of Health and Disease, for the uninitiated). The neonatal uterine environment is dependent largely on maternal nutrition and the maternal metabolism, mediated, in part, by the placenta. We know that a number of crucial micro- and macronutrients have causal relationships with developmental health and disease, as do maternal exposure to toxins, such as alcohol. Maternal nutrition constitutes a large part of the neonatal exposome, or the sum total of substances to which a developing neonate is exposed.
Nutrition can have a causal impact on epigenetic phenomena like DNA methylation. In particular, folate metabolism has been extensively investigated as a causal player in DNA methylation at some loci in humans. Further, studies have shown an association between epigenetic variation in the brain and late-onset mental illnesses like schizophrenia, as well as with early life neurodegenerative disorders like Rett Syndrome. Perhaps unsurprisingly, epigenetic influences are now under exploration with respect to their role in obesity, adiposity, and metabolism.
Maternal Metabolism and Epigenetics
What types of mechanisms dictate how nutrition modulates gene expression, and how do they affect health outcomes?
Gillman et al. suggest that neonatal glucocorticoid exposure may pre-program body fat distribution in humans, and further studies have shown that fetal hormonal exposure affects insulin resistance and other metabolic indicators in animal models. Maternal malnutrition (both over- and under-nourishment), access to key micronutrients, and maternal metabolic state appear to affect adiposity and metabolism of the offspring.
Maternal under-nutrition, in particular, is implicated as a major source of epigenetic influence for offspring obesity. In keeping with the DoHAD hypothesis, analysis of data from survivors of the Dutch Hunger Winter of 1944-45 who suffered periconceptual exposure to famine conditions suggest a possible epigenetic mechanism for the influence of prenatal nutrient availability on obesity and metabolic disorders in later life: early neonatal exposure to famine conditions in this population is associated with a number of epigenetic modifications linked to aberrant fat distribution and obesity. Comparisons among same-sex siblings not subjected to prenatal famine conditions showed differential DNA methylation at a number of loci.
While it is difficult to establish a causal relationship from Dutch Hunger Winter data, this strongly suggests that prenatal famine conditions could be related to metabolic developmental epigenetics. Kirkbride et al. postulates one-carbon metabolism as a mechanism by which prenatal folate availability might affect epigenetic control at number of relevant loci.
While it’s intuitive that low birth weight babies such as those in the Dutch Hunger Winter study show an altered metabolic phenotype later in life, subsequent studies have also noted a relationship between exceptionally high birth weight babies and the development of obesity, diabetes, and glucose intolerance. Dr. Chittaranjan S. Yajnik points out that maternal obesity is a strong predictor (though not determinant) of offspring obesity and diabetes incidence.
Maternal nutrition during pregnancy is one avenue of epigenetic programming for the future health of offspring, but variation in maternal metabolism is also predictive of obesity and impaired glucose tolerance for neonates. Early investigations into how metabolism might be inherited called this process “fuel-mediated teratogenesis,” and we now understand that epigenetic influences are involved in obesity in addition to possible genetic determinants. Of course, maternal nutrition and metabolism aren’t the only influences on neonatal epigenetic programming: exposure to toxins like endocrine disruptors (BPA) and maternal stress (glucocorticoid exposure) are also under exploration as they relate to epigenetic mechanisms of metabolic disease.
So What?
It’s worth keeping in mind that obesity and metabolic diseases are multifactorial, with genetic, epigenetic, and/or exposure-related components of pathogenesis. However, the results of the investigations discussed here stand contra to the widely-held assumptions that obesity is purely a matter of agency on the part of an affected individual, or that adult access to healthy food can overcome obesity in every circumstance.
It is clear that the developmental origins of obesity and metabolic disorders can pre-program our metabolism and our predisposition to obesity; that is, our ability or inability to maintain a healthy weight in adulthood may be determined by our placental environment and by intrauterine factors long before we have any control over our eating or exercise habits.
While this might sound bleak with respect to reining in the obesity epidemic, evidence from epigenetic investigations can productively inform public health initiatives to prevent obesity more efficiently and effectively. For example, greater attention to maternal nutrition and to the overall nutrition of young women of child-bearing age presents a viable target for intervention as DoHAD mechanisms become better elucidated: whole generations of neonates could be spared a predisposition to obesity.
Until we better understand the relationships among maternal nutrition, metabolism, and epigenetic modification, exactly what form these interventions should take remains unclear. The growing body of literature on epigenetics does suggest that neonatal nutrition and other kinds of chemical exposure continue to affect the epigenome long after we’re born, and investigations are underway to further characterize these interactions and their long-term effects.
- The Epigenome: Nutrition and Metabolic Health - July 12, 2016
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