The developmental origins of adult disease

Abstract

Epidemiological and clinical observations have led to the hypothesis that the risk of developing some chronic diseases in adulthood is influenced not only by genetic and adult lifestyle factors, but also by environmental factors acting in early life. These factors act through the processes of developmental plasticity and possibly epigenetic modification, and can be distinguished from developmental disruption. The concept of predictive adaptation has been developed to explain the relationship between early life events and the risk of later disease. At its base, the model suggests that a mismatch between fetal expectation of its postnatal environment and actual postnatal environment contribute to later adult disease risk. This mismatch is exacerbated, in part, by the phenomenon of "maternal constraint" on fetal growth, which implicitly provides an upper limit of postnatal nutritional environment that humans have adapted for and is now frequently exceeded. These experimental, clinical and conceptual considerations have important implications for prevention and intervention in the current epidemic of childhood obesity and adult metabolic and cardiovascular disorders.

Figure 1

The predictive adaptive model is illustrated with respect to the human food‐energy environment. For each of three scenarios, variations in the actual postnatal environmental range experienced over time (between the red lines) and that predicted by the fetus (stippled region) are shown. The embryo/fetus/neonate sets its postnatal physiology for the predicted (stippled), rather than actual range. For the ancestral hunter‐gatherer (left panel), the predicted and actual postnatal environments are similar. The upper limit of the predicted range is below that of the actual range because of maternal constraint – this creates a small region (D_a) where there is a risk of mismatch between the prenatal and postnatal environments, and hence of disease in later years (if longevity were ever great enough and the environment was consistently rich enough). The lower limit of the predicted range may or may not be below the actual range of postnatal nutrition seen – if it is, it creates a safety range of extreme conditions for which physiology can adapt. The middle panel illustrates the consequences of optimal fetal development in a modern society. The upper limit of the actual nutritional range is now shifted upward substantially. Maternal constraint continues to restrict the upper limit of predicted environmental range, creating a wider gulf between the predicted and actual postnatal environments (D_b), which increases the probability of disease risk, particularly in middle age. The right panel shows the situation when the fetus is exposed to either extreme maternal constraint or maternal/placental disease. Predictive adaptive responses reduce the upper limit of the predicted postnatal environment even further, increasing the risk of mismatch (D_c) and disease. Irreversible plastic changes with immediate adaptive value in utero may also contribute to the narrowing of the postnatal range to which the fetus can adjust.