Early life nutrition, epigenetics and programming of later life disease.

Mark Vickers

doi:10.3390/nu6062165

Abstract

The global pandemic of obesity and type 2 diabetes is often causally linked to marked changes in diet and lifestyle; namely marked increases in dietary intakes of high energy diets and concomitant reductions in physical activity levels. However, less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from altered environmental conditions during the early life period. Human and experimental animal studies have highlighted the link between alterations in the early life environment and increased risk of obesity and metabolic disorders in later life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. In particular, the nutritional environment in which the fetus or infant develops influences the risk of metabolic disorders in offspring. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, as epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. Moreover, evidence exists, at least from animal models, that such epigenetic programming should be viewed as a transgenerational phenomenon. However, the mechanisms by which early environmental insults can have long-term effects on offspring are relatively unclear. Thus far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification, and microRNA) and permanent changes in cellular ageing. A better understanding of the epigenetic basis of developmental programming and how these effects may be transmitted across generations is essential for the implementation of initiatives aimed at curbing the current obesity and diabetes crisis.

Highlights

Obesity and its metabolic sequelae may prove to be the greatest threat to human lifestyle and health in the developed world this century
The role of macronutrients is clearly implicated in developmental programming [22], maternal micronutrient levels are of interest as they are essential for the one-carbon metabolism involved in DNA methylation and an imbalance in these nutrients can influence DNA methylation patterns in offspring
It has been shown that the GLP-1 analog Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence pancreatic and duodenal homeobox factor-1 (PDX1) in the intrauterine growth restricted (IUGR)

Summary

Background

Obesity and its metabolic sequelae may prove to be the greatest threat to human lifestyle and health in the developed world this century. Epigenetics integrates microRNAs (miRNAs) and there is an emerging framework integrating genomic methylation, histone modifications and the effects of miRNAs. As above, research to date has predominantly focused on dietary related changes in DNA methylation status [15], an increasing number of reports are highlighting the role of nutrition manipulations on histone structure and function and miRNAs. Work on microRNAs has revealed a complex network of reciprocal interconnections: are they able to control gene expression at a post-transcriptional level, representing a new important class of regulatory molecules, but they are directly connected to the epigenetic machinery through a regulatory loop [16]. The phenotypic effects of epigenetic modifications during development may not manifest until later in life, especially if they affect genes modulating responses to later environmental challenges, such as post-weaning dietary challenges with energy dense diets. The extent of the developmental window for the induction of epigenetic changes in key physiologic systems is not well characterised, but he period of plasticity appears to extend from the periconceptional period into postnatal life [4,11]

Evidence from Epidemiology

Evidence from Animal Models

Transgenerational Epigenetic Programming

Conclusions