Development represents a period of rapid change in the expression of the genome, during which environmental cues may induce persistent changes in the phenotype of an organism. The developmental program tends to follow a path in which the characteristics of the wild type or typical phenotype are buffered against genetic and epigenetic change, termed canalization.15
However, many organisms respond during development to cues about their likely future environment, and this alters the developmental program and generates alternative phenotypes. Such deviation from canalized development allows production of different phenotypes from a single genotype more rapidly than could be achieved by mutation. For example, crowding of adult desert locusts (Scistocerca gregaria
) induces gregarious, diurnal and migratory offspring, in contrast to the nocturnal, sedentary forms which are produced under low population density;16
and the duration of day light to which meadow voles (Microtus pennsylvanicus
) are exposed before conception determines coat thickness in the offspring in anticipation of winter or spring temperatures.17
Such rapid changes in phenotype may facilitate short-term survival, but may also be genetically assimilated and so produce stable phenotypes on which natural selection can act.18
Increasing evidence suggests that such persistent changes in the expression of the genome involve altered epigenetic regulation of specific genes.
Gluckman and Hanson19,20
have argued that the developmental environment can produce a range of effects, from overt disruption of development (i.e. teratogenesis), through altered fetal growth, with both its immediate and later consequences, to a range of phenotypes which become manifest only well after birth. This latter class can be induced by maternally transduced cues operating even within the normal range of developmental environments but nonetheless affecting several components of the trajectory of phenotypic development. The responses do not necessarily confer any immediate advantage for the fetus but give a Darwinian fitness advantage in later environments, the nature of which is predicted on the basis of the developmental experience. As the phenotype develops, the nature of this advantage may change at different points across the life course. Thus increased insulin sensitivity may promote adipogenesis, providing nutritional reserves to protect the brain after weaning;22
earlier puberty enhances fitness in a predicted adverse environment;23,24
and the development of later insulin resistance confers a degree of “thrift” in a predicted adverse environment, as may reduction in numbers of energy-consuming skeletal and cardiac muscle cells or renal nephrons. This type of response has been termed a predictive adaptive response (PAR),25
and experimental and clinical studies supporting the concept have now been reported.26,27
According to the PARs model, the accuracy of the responses is dependent on the environment remaining relatively constant throughout the lifecourse. Although environments can fluctuate, modelling studies have shown that induced phenotypes can persist for several generations and provide an adaptive advantage in environments considered stochastically.27
Thus, the fidelity of the predictions made during early life need not be high for PARs to confer a fitness advantage and thus be selected through evolution. When the anticipated environment is effectively constant over many generations, the predictive trait/response may become fixed, or genetically encoded in a process known as genetic assimilation.28
This process may include selection of advantageous mutations.
PARs thus act as an integrated regulator in early life to establish a life-course strategy for meeting the demands of the predicted later environment29
and are only adaptive when the post-developmental environment is in the predicted range.29
If the later environment lies outside the anticipated range, the individual is “mismatched”, having a phenotype which is not appropriate for that environment. This can affect a range of traits including abdominal fat deposition, reduced skeletal muscle deposition, reduced endothelial function, fewer cardiomyocytes, fewer nephrons, earlier puberty (at least in females), alterations in Th1
cell balance associated with atopic/allergic reactions, reduced DNA repair leading to earlier ageing, and a range of effects on behaviour, including affective disorders and stress responses which are sex specific.30,31
It is important to note that neither the developmental nor the later environment need to provide extreme challenges, only that the phenotype induced by the former is not optimal for responding on a long-term basis to the latter.
Mismatch can arise through a range of circumstances. It can result from exposure to an environment which is evolutionarily novel and thus beyond the predictive capacity of the fetus. Indeed, the contemporary diets and lifestyles of developed societies constitute such a novel environment for Homo sapiens
. The risk of NCD is then related to the degree of mismatch rather than to the absolute level of the adult environment per se
. This is demonstrated in a number of experimental studies in which pre- and postnatal diets were manipulated.32-34
For example, male sheep exposed to prenatal undernutrition but normal postnatal diet, and vice versa
, showed altered cardiovascular function which was absent in animals subjected solely to undernutrition.35
In rats exposed to a high-fat diet in utero
, endothelial dysfunction was observed in offspring fed a normal post-weaning diet, but not in those fed a high-fat post-weaning diet.36
The degree of mismatch can by definition be increased by either poorer environmental conditions during development, or richer conditions later, or both.37
Unbalanced maternal diet, body composition or disease can perturb the former; a rapid increase in energy-dense foods and reduced physical activity levels associated with a western lifestyle will increase the degree of mismatch via the latter (). Such changes are of considerable importance in developing societies going through rapid socio-economic transitions.
Developmental influences on vulnerability to metabolic disease