Presented at the Neonatal Society 2005 Spring Meeting.

Hanson MA

Centre for Developmental Origins of Health & Disease, University of Southampton, UK

The epidemic of obesity in developed and in some developing societies brings an enormous burden of chronic cardiovascular, metabolic and bone and joint disease, which will have tremendous economic and humanitarian cost. Prevention is difficult if causes are not known. The speed of development of this problem excludes a purely genetic origin, although early environmental influences on gene expression must be involved. It results from environmental change, hence its prominence in populations in transition. The changing environment relates to nutrition, and the balance between energy expenditure and calorific intake. The role of the developmental environment in such disease has been known for many years. Previous theories to account for these effects concerned a thrifty genotype or phenotype. A new focus concerns the role of predictive adaptive responses (PARs) (1). These are induced by cues from the mother about the external environment. They utilise in part the processes of maternal constraint. They operate to a degree in all pregnancies, not just when fetal growth is reduced. They may also operate during suckling. During evolution they conferred survival advantage in an uncertain nutritional environment. But when the predictions are inappropriate, e.g. in a modern energy-rich environment, they are associated with greater risk of later disease. Maternal constraint is related to maternal size and is more marked in primiparous pregnancy, in teenage and older women, and in twins. It is also increased in maternal disease and placental insufficiency. All these processes increase the risks of inappropriate PARs. It is important to stress that PARs confer no immediate advantage to the embryo or fetus, and are not solely associated with reduced prenatal growth. In this respect they differ from the thrifty phenotype. The mechanisms involved include epigenetic gene-environment interactions, e.g. changes in DNA methylation. In addition gene polymorphisms conferring susceptibility to disease become apparent when coupled with prenatal restriction of growth. Animal studies show that both the metabolic and the cardiovascular effects of an impaired intrauterine environment can be passed across two or more generations, questioning traditional ideas about ‘inherited’ components of disease risk.

Acknowledgements: MAH is supported by the British Heart Foundation

References
1. Gluckman PD and Hanson MA (2004). The Fetal Matrix. Cambridge University Press