Impact of maternal diet on the epigenome and potentially modifiable effects on offspring health

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Our experiences in early life can have life-long effects on our health and wellbeing. For example, in a rural population in The Gambia in West Africa we have observed that children born in the rainy season are 6 times more likely to die between the ages of 15 and 65 than those born in the dry season. In fact there is mounting evidence that detrimental influences on lifelong health can stretch right back to the early stages of embryonic development. This underlines the importance of research into the underlying mechanisms, so that the processes linking environmental exposures to negative outcomes can be understood, and hopefully corrected.One such possible mechanism involves a process known as methylation, which is one type of 'epigenetic' modification of the genome. Methylation requires a defined set of nutrients including folic acid and B-vitamins, both to provide the necessary chemical compounds, known as methyl groups, and to undertake the necessary metabolic conversions. Animal experiments have previously shown that supplementing the diets of female mice with these nutrients before they conceive has a profound effect on their offspring's appearance (e.g. changing their coat colour) and that these changes were associated with higher levels of methylation on their DNA. Until now it was unknown whether similar effects on offspring methylation occur in humans, but our group recently presented first-in-human evidence that they do. We have since followed up this work by looking at patterns of methylation across the genome. We found evidence of unusual or 'disrupted' methylation patterns associated with both maternal nutrient status and season of conception in certain types of genes, and notably in one gene (VTRNA2-1), where disrupted methylation has previously been linked with some forms of cancer and also with negative effects on the immune system.With this grant we hope to extend this work in a number of ways. Firstly, we want to characterise these patterns of disruption more precisely by looking at a larger number of infants; interrogating key regions of the epigenome at high resolution using more advanced technologies; and looking for methylation effects all the year round. We hope this will provide further clues about the mechanisms underlying epigenomic disruption. Secondly, we want to investigate the effects of disrupted methylation in VTRNA2-1. Our Gambian research centre is a particularly good place to do this as we are able to link an individual's epigenetic information with medical records and other demographic data, and we can also conduct detailed laboratory investigations on blood cells in individuals known to have abberant methylation. These functional studies are an important part of the chain linking epigenetic effects to real, adverse health outcomes in people. Finally, with the help of advanced computer modelling, we will identify the specific combination of MD-related nutrients that may be causing the observed patterns of disrupted methylation. We will then develop a nutritional supplement to correct the observed suboptimal nutrient profile, and we will test its effectiveness in a randomised controlled trial. If effective, in future work we would seek to assess the effect on offspring methylation of giving this supplement to mothers-to-be. The hope is that the patterns of disrupted methylation previously observed in infants conceived at certain times of the year would then be prevented. In the longer term, we hope that the work described here will inform strategies for pre-conceptional supplementation in mothers that will lead directly to improved outcomes for infant growth and development, with life-long benefits for health and wellbeing.