Important studies undertaken predominantly in the UK during the 1990s showed an association between being born small and an increased risk of developing coronary heart disease, type 2 diabetes, the metabolic syndrome and osteoporosis in later life. These studies led to the ‘developmental origins of health and disease (DOHaD)’ hypothesis; which suggests that exposure to an ‘adverse environment’ during early life determines disease susceptibility in later life. Further studies have confirmed these findings and extended our understanding of the longer term consequences to include effects on stress hormones, behaviour and psychiatric disease risk. In terms of what such an adverse environment might be, many reports suggest that poor or unbalanced maternal nutrition, overnutrition (e.g. maternal obesity), smoking or maternal stress might all have consequences for a developing baby. 

We are starting to understand the mechanisms by which the early environment ‘programmes’ disease risk. Scientists working with mice and rats have shown that changes in the size or function of particular organs might lead to an increase in disease risk. For example, studies suggest that maternal malnutrition can result in poor kidney development during fetal life, and since the kidney is particularly important in blood pressure control, this can predispose an individual to developing high blood pressure. There has also been much recent interest in whether programmed effects can be mediated through changes in chemical marks on our genes which affect how they work – so called ‘epigenetic’ effects. Some of our own recent work has shown that if a woman smokes during pregnancy, we can detect alterations in epigenetic marks in the developing fetus. Similarly, we have shown that if a mother eats an unbalanced diet during pregnancy, we can detect effects on her children’s epigenome some 40 years later. 

However, not surprisingly, it’s not all down to what your mother experiences during pregnancy. Some very new studies suggest that the father also plays a role and that his experiences might cause epigenetic changes in his sperm that can affect the development of his children. Studies which have been carried out in rats, mice and even flies suggest that paternal diet or stress might affect epigenetic marks in sperm, leading to adverse health effects in his children. However, things don’t stop there. It appears that these effects on disease risk can be passed through generations, from grandparents to children and then grandchildren (and possibly further). Studies in a population from Overkalix in Northern Sweden showed that the diet of grandparents affected the health of their grandchildren many years later. Reports from long term follow-up of families involved in the Dutch Hunger Winter (a short period during the Second World War when a part of Amsterdam was affected by acute food shortages) suggest that acute malnutrition affecting women during pregnancy had effects not only on her children but also on her grandchildren. Again, in order to try and tease out the mechanisms, studies have been performed in rats and mice. These have suggested that epigenetic changes which are transmissible through eggs and sperm might mediate these ‘intergenerational’ effects.  

These effects on disease risk are important. Cardiovascular disease is the biggest killer of men in the UK and the second biggest for women and is a significant burden on health care costs. Although current healthcare interventions are mainly focused on the prevention and treatment in adulthood, research in the DOHaD field suggests that these diseases may originate from very early in life. If we could identify who is at risk at an early stage – at birth or in childhood for example, we may be able to design and target interventions which would reduce the risk of many of these diseases, meaning that people would live longer and healthier lives. Additionally, perhaps we could intervene to prevent the transmission of effects across generations, resulting in healthier lives for our children and grandchildren. 

Dr Mandy Drake

Reader and Scottish Senior Clinical Fellow, University of Edinburgh

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