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Mechanisms of Disease: the developmental origins of disease and the role of the epigenotype

Abstract

There is accumulating evidence that many chronic diseases such as type 2 diabetes and coronary heart disease might originate during early life. This evidence gives rise to the developmental origins of disease hypothesis, and is supported by epidemiological data in humans and experimental animal models. A perturbed environment in early life is thought to elicit a range of physiological and cellular adaptive responses in key organ systems. These adaptive changes result in permanent alterations and might lead to pathology in later life. Aging organs and cells seem therefore to retain a 'memory' of their fetal history and adaptive responses. The mechanisms underlying the developmental origins of disease remain poorly defined. Epigenetic tagging of genes, such as DNA methylation and histone modification, controls the function of the genome at different levels and maintains cellular memory after many cellular divisions; importantly, tagging can be modulated by the environment and is involved in onset of diseases such as cancer. Here we review the evidence for the developmental origins of disease and discuss the role of the epigenotype as a contributing mechanism. Environmentally induced changes in the epigenotype might be key primary events in the developmental origins of disease, with important clinical implications.

Key Points

  • Individuals with a low birth weight are at increased risk of developing type 2 diabetes, cardiovascular disease and the metabolic syndrome later in life

  • The fetal environment has a key role in mediating the relationship between early growth and adult disease

  • Epigenetic states can influence cellular physiology and affect disease risk and severity through associated chromatin and gene activity changes

  • Programmed changes in the epigenotype represent a major candidate molecular mechanism by which the early environment can lead to permanent changes in the phenotype

  • The identification of epigenotypes predictive of disease susceptibility would enable targeted intervention strategies to be employed

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Figure 1: The developmental programming hypothesis
Figure 2: The epigenotype

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Acknowledgements

SE Ozanne is a British Heart Foundation Lecturer and M Constância is a David Phillips Fellow (Biotechnology and Biological Sciences Research Council). The Authors would like to thank Dr I Sandovici and Dr N Smith for their help and critical reading of the manuscript.

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Correspondence to Susan E Ozanne.

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Ozanne, S., Constância, M. Mechanisms of Disease: the developmental origins of disease and the role of the epigenotype. Nat Rev Endocrinol 3, 539–546 (2007). https://doi.org/10.1038/ncpendmet0531

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