Children whose mothers ate badly during pregnancy grow up with a higher risk of diabetes because poor maternal diets change the way critical genes are switched on and off in their body, new research has suggested.
A study of rats has found the first direct evidence that a mother’s diet alters the activity of a gene that plays an important role in insulin production and type 2 diabetes. The findings, from scientists at the University of Cambridge, offer strong indications that similar processes explain why the conditions a child experienced in the womb can have a lasting influence on adult health.
The impact of a mother’s diet on the later health of her offspring has been established by many previous studies, which have linked poor nutrition during pregnancy to a raised risk of type 2 diabetes, cardiovascular disease, high blood pressure, and even psychiatric disorders and some cancers.
Some of the most remarkable evidence has come from research into Dutch children born during the “Hunger Winter” famine of 1944, when Nazi Germany imposed a food blockade on the Netherlands. After being small at birth, they grew up to have much higher rates of obesity, diabetes and other medical problems, and the increased risk was also passed on to their own children.
Scientists have long thought that these effects are caused by a phenomenon known as epigenetics, by which genes become tagged with chemical markers in response to environmental factors. This switches them on or off or turns their activity up or down.
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The new study, published in the journal Proceedings of the National Academy of Sciences, has shown for the first time that poor maternal diet can indeed induce such epigenetic effects in a manner that influences a disease.
In the study, two groups of rats were on either a normal diet or a diet reduced in protein. The malnourished rats were more likely to develop diabetes as they aged. The scientists analysed DNA from the beta cells of the pancreas that make insulin in both young and old rats, to look for epigenetic changes.
These experiments showed that the malnourished rats had epigenetic modifications in a gene called HNF alpha, which is important to beta cell growth. Mutations in this gene have been linked to diabetes in humans. The epigenetic marks slowed the malnourished rats’ ability to make insulin, which worsened as the animals grew older.
“We know that a mother’s diet has a substantial impact on the offspring’s health,” said Susan Ozanne, who led the research. “But while the associations are clear, we didn’t really understand what the mechanisms are by which the environment is sensed and thus has an effect.
“What’s most exciting about these findings is that we are now starting to really understand how nutrition during the first nine months of life spent in the womb shape our long-term health, by influencing how the cells in our bodies age.”
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Her colleague, Miguel Constancia, said that while rats are not humans, the findings are relevant for people because epigenetic effects on gene activity tend to be reasonably similar in mammals. “These changes may explain why a poor diet in pregnancy leads to [a child’s] increased risk of diabetes later in life.”
He said it was difficult to draw precise lessons for human nutrition during pregnancy, other than to recommend a balanced diet.
Asked whether he expected this effect to be seen in human populations, Dr Constancia said: “That’s the expectation. The study was conducted in rats but we have reason to believe this sort of situation will apply to other species. Why not? Epigenetic regulation seems to be highly conserved.”
Dr Ozanne said the findings could explain some of the health problems seen in Dutch children born during the Hunger Winter. “It’s absolutely a reasonable hypothesis. If you look at the islets of people with type 2 diabetes, they have very low levels of HNF alpha. Not all of that will be because of poor maternal diets but it does suggest that there may be an influence.”
It is impossible to repeat the study directly in humans for ethical and practical reasons: it is extremely difficult to remove beta cells from the pancreas without harming people. The researchers, however, are now looking for epigenetic changes in beta cells from people who have died in road accidents.
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“We’ve literally just started a study of human islets, from individuals who unfortunately died in road traffic accidents, aged between 15 and 74,” Dr Ozanne said. “We’re looking to see if the rate of epigenetic changes increases with age as we expect.”
Dr Constancia said it could eventually be possible to develop drugs that correct epigenetic changes, though these will have to be carefully targeted at particular genes to be safe.
“The problem is that drugs affect the entire genome, and we haven’t yet found ways to target specific genes and epigenetic markers,” he said. “What’s exciting about this field is that hopefully we will be able to do so, to reversibly take out these epigenetic markers in a gene-specific way. But that is far down the future.”