Biomedical science has little considered the relevance of life history theory and evolutionary and ecological developmental biology to clinical medicine. However, the observations that early life influences can alter later disease risk--the "developmental origins of health and disease" (DOHaD) paradigm--have led to a recognition that these perspectives can inform our understanding of human biology. We propose that the DOHaD phenomenon can be considered as a subset of the broader processes of developmental plasticity by which organisms adapt to their environment during their life course. Such adaptive processes allow genotypic variation to be preserved through transient environmental changes. Cues for plasticity operate particularly during early development; they may affect a single organ or system, but generally they induce integrated adjustments in the mature phenotype, a process underpinned by epigenetic mechanisms and influenced by prediction of the mature environment. In mammals, an adverse intrauterine environment results in an integrated suite of responses, suggesting the involvement of a few key regulatory genes, that resets the developmental trajectory in expectation of poor postnatal conditions. Mismatch between the anticipated and the actual mature environment exposes the organism to risk of adverse consequences-the greater the mismatch, the greater the risk. For humans, prediction is inaccurate for many individuals because of changes in the postnatal environment toward energy-dense nutrition and low energy expenditure, contributing to the epidemic of chronic noncommunicable disease. This view of human disease from the perspectives of life history biology and evolutionary theory offers new approaches to prevention, diagnosis and intervention.

Cellular commitment to a specific lineage is controlled by differential silencing of genes, which in turn depends on epigenetic processes such as DNA methylation and histone modification. During early embryogenesis, the mammalian genome is 'wiped clean' of most epigenetic modifications, which are progressively re-established during embryonic development. Thus, the epigenome of each mature cellular lineage carries the record of its developmental history. The subsequent trajectory and pattern of development are also responsive to environmental influences, and such plasticity is likely to have an epigenetic basis. Epigenetic marks may be transmitted across generations, either directly by persisting through meiosis or indirectly through replication in the next generation of the conditions in which the epigenetic change occurred. Developmental plasticity evolved to match an organism to its environment, and a mismatch between the phenotypic outcome of adaptive plasticity and the current environment increases the risk of metabolic and cardiovascular disease. These considerations point to epigenetic processes as a key mechanism that underpins the developmental origins of chronic noncommunicable disease. Here, we review the evidence that environmental influences during mammalian development lead to stable changes in the epigenome that alter the individual's susceptibility to chronic metabolic and cardiovascular disease, and discuss the clinical implications.

Developmental plasticity in response to environmental cues can take the form of polyphenism, as for the discrete morphs of some insects, or of an apparently continuous spectrum of phenotype, as for most mammalian traits. The metabolic phenotype of adult rats, including the propensity to obesity, hyperinsulinemia, and hyperphagia, shows plasticity in response to prenatal nutrition and to neonatal administration of the adipokine leptin. Here, we report that the effects of neonatal leptin on hepatic gene expression and epigenetic status in adulthood are directionally dependent on the animal's nutritional status in utero. These results demonstrate that, during mammalian development, the direction of the response to one cue can be determined by previous exposure to another, suggesting the potential for a discontinuous distribution of environmentally induced phenotypes, analogous to the phenomenon of polyphenism.developmental plasticity ͉ epigenetics ͉ gene expression ͉ leptin ͉ obesity

No abstract

That there is a heritable or familial component of susceptibility to chronic non-communicable diseases such as type 2 diabetes, obesity and cardiovascular disease is well established, but there is increasing evidence that some elements of such heritability are transmitted non-genomically and that the processes whereby environmental influences act during early development to shape disease risk in later life can have effects beyond a single generation. Such heritability may operate through epigenetic mechanisms involving regulation of either imprinted or non-imprinted genes but also through broader mechanisms related to parental physiology or behaviour. We review evidence and potential mechanisms for non-genomic transgenerational inheritance of 'lifestyle' disease and propose that the 'developmental origins of disease' phenomenon is a maladaptive consequence of an ancestral mechanism of developmental plasticity that may have had adaptive value in the evolution of generalist species such as Homo sapiens.