Mother's diet alters coat colour of baby mice 1/8/03. By Duke University Medical Center Dietary nutrients lead to DNA methylation of coat colour gene.

A startling scientific discovery about nutrition demonstrates that we are more than what we eat: we are likely what our mothers ate, too, according to scientists at the Duke Comprehensive Cancer Center.

In a study of nutrition's effects on development, the scientists showed they could change the coat colour of baby mice simply by feeding their mothers four common nutritional supplements before and during pregnancy and lactation. Moreover, these four supplements lowered the offspring's susceptibility to obesity, diabetes and cancer.

"We have long known that maternal nutrition profoundly impacts disease susceptibility in their offspring, but we never understood the cause-and-effect link," said Randy Jirtle, senior investigator of the study. "For the first time ever, we have shown precisely how nutritional supplementation to the mother can permanently alter gene expression in her offspring without altering the genes themselves."

Pregnant mice that received dietary supplements with vitamin B12, folic acid, choline and betaine (from sugar beets) gave birth to babies predominantly with brown coats. In contrast, pregnant mice that did not receive the nutritional supplements gave birth predominantly to mice with yellow coats. The non-supplemented mothers were not deficient in these nutrients.

A study of the cellular differences between the groups of baby mice showed that the extra nutrients reduced the expression of a specific gene, called Agouti, to cause the coat colour change. Yet the Agouti gene itself remained unchanged.

Just how the babies' coat colours changed without their Agouti gene being altered is the most exciting part of their research, said Jirtle. The mechanism that enabled this permanent colour change - called 'DNA methylation' - could potentially affect dozens of other genes that make humans and animals susceptible to cancer, obesity, diabetes, and even autism, he said.

"Our study demonstrates how early environmental factors can alter gene expression without mutating the gene itself," said Rob Waterland, lead author of the study. "Methylation is a common event in the human genome, and it is clearly a malleable effect that is subject to subtle changes in utero."

During DNA methylation, a quartet of atoms - called a methyl group - attaches to a gene at a specific point and alters its function. Methylation leaves the gene itself unchanged. Instead, the methyl group conveys a message to silence the gene or reduce its expression inside a given cell. Such an effect is referred to as ‘epigenetic’ because it occurs over and above the gene sequence without altering any of the letters of the genetic code.

In the treated mice, one or several of the four nutrients caused the Agouti gene to become methylated, thereby reducing its expression – and potentially that of other genes, as well. Moreover, the methylation occurred early during gestation, as evidenced by its widespread manifestation throughout cells in the liver, brain, kidney and tail.

"Our data suggest these changes occur early in embryonic development, before one would even be aware of the pregnancy," said Jirtle. "Any environmental condition that impacts these windows in early development can result in developmental changes that are life-long, some of them beneficial and others detrimental." If such epigenetic alterations occur in the developing sperm or eggs, they could even be passed on to the next generation, potentially becoming a permanent change in the family line, added Jirtle.

Methylating a single gene can have multiple effects. For example, the Agouti gene regulates more than just coat colour. Mice that over-express the Agouti protein tend to be obese and susceptible to diabetes because the protein also binds with a receptor in the hypothalamus and interferes with the signal to stop eating. Methylating the Agouti gene in mice, therefore, also reduces their susceptibility to obesity, diabetes and cancer.

"Diet, nutritional supplements and other seemingly innocuous compounds can alter the development in utero to such an extent that it changes the offspring's characteristics for life, and potentially that of future generations," said Waterland.

Adapted from a press release by Duke University Medical Center.

Further reading

Waterland RA and Jirtle RL.Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003 Aug;23(15):5293-300. Full text