Published online 2 June 2006 | Nature | doi:10.1038/news060529-10

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Dietary supplement can make generations of mice obese.

Can too many vitamins be bad for a pregnant mom? © Punchstock

A simple vitamin supplement in a pregnant mouse's diet can make her offspring fatter, according to research presented on 1 June at the Human Genome Organisation meeting in Helsinki, Finland. The effect is thought to be due to chemical changes made to the mother's DNA, which can be passed down the generations.

The study adds to the debate over whether it's a good idea for expectant mothers to up their dietary intake of folic acid, a common supplement used to help lower the incidence of spina bifida.

Rob Waterland and his team at the Baylor College of Medicine in Houston, Texas studied the effects of certain compounds in food, including folic acid and vitamin B 12 . These compounds are known to add chemical constituents called methyl groups to DNA, which affects the activity of genes: part of a phenomenon called 'epigenetics'.

Other researchers had already shown that adding methyl donors to a female mouse's diet can influence gene activity in her pups. In mice with a mutation in a coat-colour gene called agouti (the mutation is called agouti variable yellow, or Avy), supplementing the diet of pregnant females turns their pup's coats from yellow to brown. Waterland's team later showed that the supplements did this by methylating a bit of DNA that regulates the agouti gene, which effectively turns off the abnormal gene activity caused by the mutation.

Avy mice are also obese. So Waterland's team wanted to see whether this too could be altered by epigenetics.

Feed me

The researchers fed Avy females methyl-donating chemicals in the form of folic acid, vitamin B 12 , betaine and choline. They collected and weighed their pups, and then repeated the experiment: feeding methyl donors to the female pups and then looking at their offspring. They expected to find that pup weight decreased over the generations as the animals inherited and acquired more and more methylation of their Avy mutation, which would be expected to turn down the agouti gene's activity.

Instead, they found the opposite: the mice got heavier down the generations. What's more, when they repeated the experiment with non-Avy mice, they got similar results.

Vitamin supplements wouldn't be expected to affect the weight of pups, particularly not in a way that accumulates from one generation to the next, just from their nutritional value alone. So methylation of some as-yet-unknown gene, the researchers say, is the most likely explanation for the heritable weight gain.

David Barker of Southampton University, an expert on the fetal origins of adult disease, says the findings give new insight into how maternal nutrition could affect the fetus. "This rapid rise of epigenetics is making sense of what we have been working on for the past 20 years," he says. "We know that the human embryo is extremely sensitive to the nutritional environment."

The doses of methyl donors given to the mice were comparable to those taken by people who use vitamin supplement tablets, says Waterland. "This raises the question, can too many vitamins be bad for us?" he asked the conference.

Fortified diet

Women planning a pregnancy are advised to take folic acid supplements because they drastically reduce the chances of having a baby with neural tube defects such as spina bifida. Some countries, including the United States, have introduced mandatory fortification of grains and flour to bump up the folic acid levels in women across the board.

Neural tube defects in the United States have dropped sharply thanks to mandatory fortification. But there is fierce debate over whether this is a good idea. There is a complex relationship between dietary exposure to folic acid and the risk of developing certain cancers, for example.

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The emerging picture from studies of how methyl donors in a mouse's diet can influence her offspring's gene expression and weight will add an extra dimension to this debate.

Waterland emphasizes that there is currently no evidence that folic acid can have these sorts of effects all by itself. All the studies so far have used combinations of different methyl donors, and they have all been in mice. So it is too early to draw any conclusions about the effects of folic acid in humans. "I think it's premature at this point," he says. Waterland's team is investigating further.

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