The fetal, neonatal, and infant environments—the long-term consequences for disease risk
Section snippets
A conceptual and evolutionary synthesis
These ideas were the basis of the “thrifty phenotype hypothesis” [5]. This stated that the fetus responded to an adverse environment by making irreversible changes in its developmental trajectory and, in particular, by reducing its growth. The reduced fetal growth enabled the fetus to conserve the limited energy available for cardiac function and neural development, but there was a “tradeoff.” The intrauterine exposure to a deprived environment had channeled development in such a way that the
Developmental plasticity
An understanding of developmental plasticity allows elucidation of these concepts [11]. It is useful to distinguish between developmental plasticity and disruption—developmental plasticity describes normal processes that allow a range of phenotypes to develop from a single genotype, whereas the latter involves disruption of the developmental program—although the distinction is not sharp. Some environmental cues during development are sufficiently severe to disrupt development; these may lead to
Predictive adaptive responses (PARs)
As we have already suggested, there are adaptive responses that may be made by the developing organism in response to the environment, which have no obvious immediate adaptive value but are made in expectation of the future environment. In locusts, a commitment to a wing shape and metabolism appropriate for the migratory or solitary form is made at the larval stage in response to pheromone signals [10]. There is no advantage either way to the larva, but to develop as the solitary form in a
A conceptual synthesis
Thus, a model to explain the “developmental origins of adult disease” phenomenon has evolved (see Fig. 1). It is suggested that the relationship between the predicted and actual mature environments determines disease risk [16]. If there is a match, then the disease risk is low. If there is a mismatch, then disease risk is greater. Disease risk is created because the physiological settings established during the plastic and predictive phases are not appropriate for the environment confronted in
The role of genetic factors
It is the gene–environment interaction that determines the impact of any environmental challenge. The outcome of that interaction can be affected by both the environmental cue and the genotype. Thus, it is not surprising that polymorphisms in key genes can determine the impact of a cue in terms of the nature or presence of an adaptive response. If one cannot hear, one cannot respond to an auditory cue. If the impact of a metabolic signal is affected by genetic variation in the signalling
Prematurity as a programming stimulus
The thrifty phenotype hypothesis and the epidemiological observations focused attention on impaired fetal nutrition and accompanying reduction in fetal growth as central to the hypothesis. The progressive understanding of the mechanisms of developmental plasticity and the broader dimensions of the programming phenomenon broaden the focus beyond impaired fetal growth. We have already pointed out that the phase of plasticity extends from conception to after birth. Altered growth is but one
Fetal versus infant induction of programming
Birth is, in some ways, simply an environmental transition in the continuous process of human development. There is no inherent reason why the induction of PARs is restricted to fetal life because it can occur while windows of plasticity are open. There is good evidence that this can be achieved by behavioural or nutritional manipulation in the rat pup. As late gestational stimuli can influence lifelong outcomes in humans (e.g., the consequence of third trimester undernutrition during the Dutch
An evolutionary perspective
Developmental plasticity has been essential for evolution of species because different phenotypes are more appropriate for one environment than another. We have suggested that programming is a result of the channeling of developmental plasticity by the processes of adaptive responses to promote the match between the developmental and the later environments. It can be induced over a broad period, depending on the system, provided the processes of epigenesis and developmental plasticity still
Final comments
The implications of this biology are still to be fully understood. While the presence of the phenomenon is unequivocal, there is still debate as to the relative importance of programming for the incidence of disease, as opposed to risk factors for disease. There is only one population estimate based on a Finnish cohort and it suggests a major effect [54]. The difficulty in the estimate is compounded by the growing recognition that mismatch can occur at various periods of fetal or infant growth:
Acknowledgements
M.A.H. is supported by the British Heart Foundation. We thank Dr. C. Pinal for her assistance with the manuscript.
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