The Developmental Origins of Health and Disease

Introduction

An association between the early life environment and health in later life has been known at least since the time of Hippocrates. Contemporary research in this field grew following on from the seminal work of David Barker and colleagues in England in the 1980s. Barker found that the geographical pattern of adult ischaemic heart disease mortality matched that of infant mortality several decades earlier. The most common cause of infant mortality at the time was low birth weight, leading to the ‘Barker hypothesis’ that exposure to an intrauterine environment leading to poor fetal growth caused metabolic changes that persisted into adulthood and increased the risk for ischaemic heart disease.

This initial work was then validated across several populations and continuing refinement led to the coining of the term ‘fetal origins of adult disease’. Further work extended this theory, and it became evident that early life impacts upon later life disease were not limited to pregnancy but also the maternal preconception environment and early postnatal life. Gluckman and Hanson first described the DOHaD theory to better incorporate these influences outside of the fetal period upon adult health.

Much scientific research now focuses on DOHaD across a wide range of fields from both clinical and basic science arenas, and complex analysis of associations has led to new frontiers in statistics. The implications of the research extend now to the development of public health policy and global recommendations about pregnancy and childhood care. A large current thrust of the research focuses upon identifying the underlying biology of DOHaD in the hope that this might identify novel approaches to the prevention of the associated adult diseases. It is now clear that complex gene–environment interactions lie at the heart of this process.

History of the Developmental Origins of Health and Disease Theory

The Barker Hypothesis

It was not for another decade that, with the recognition in 1986 by Barker and colleagues of an association between low birth weight and adult cardiovascular disease, this area began to receive substantial research interest. In his analysis of trends in mortality across geographical regions of England and Wales, Barker found that the areas with the highest mortality rates due to ischaemic heart disease were the same as those that had the highest rates of infant mortality decades earlier. The most common cause of infant death at the time was ‘low birth weight’, and the ‘Barker hypothesis’ was formulated, suggesting that events contributing to low birth weight also contributed to the development of cardiovascular disease in adulthood ( Fig 47.1 ). Reflection upon previous research and the continued work of Barker and others developed this theory by confirming these associations across various cohorts.

Mechanisms of the Developmental Origins of Health and Disease

One principle underlying the DOHaD phenomenon is that of ‘developmental plasticity’, the notion that a range of phenotypes can result from the same genotype as a result of altered environmental exposures during an organism’s development. In the human and in the DOHaD realm, this plasticity manifests as altered disease risk in later life. The association with low birth weight does not necessarily reflect a causal role of abnormal fetal growth in the development of disease but, rather, abnormal fetal growth is but one measure of an abnormal intrauterine environment, exposure to which induces phenotypic variation leading to increased disease risk. Developmental plasticity is a well-recognised phenomenon in nonhuman species, with substantial animal evidence of the environmental impact upon gene expression and phenotype.

Plasticity is time dependent and can only take place during critical periods of organogenesis. For example, brain development takes place over a longer period than cardiac development, and environmental impacts only result in changes to cardiac structure when present during earlier development compared with those which may produce neurologic changes. Periods of plasticity may vary between the structural and functional development of an organ, however. For example, although structural development of the fetal heart is complete relatively early in gestation, late insults may alter terminal cardiac myocyte differentiation, leading to more subtle functional changes. The physiological regulation of metabolism and inflammation is relatively late to develop and is therefore subject to environmental influences for much of the early life period and more susceptible to perturbations resulting in later disease.

Gluckman and Hanson describe an important distinction in this observation, that between developmental adaptation and developmental disruption. Not all plasticity results in advantageous changes for the developing organism, and in some cases, changes are the result of environmental damage to normal developmental processes, as in teratogenesis. It is important to consider that deleterious effects of environment on phenotype may represent subtle changes resulting from developmental disruption rather than an adaptation to better suit an environment. Experimental evidence must take this into account; however, developmental plasticity which occurs at a certain point may confer an advantage at one point but a change in environment may render that adaptation harmful, especially if it occurs after the window of plasticity, preventing a reversal of the phenotypic expression. This trade-off is the basis of the thrifty phenotype hypothesis.