A mother's nutrition can be so important that it can alter her offspring's susceptibility to disease by changing gene expression, say researchers who claim to have explained for the first time how maternal nutrition can predetermine risk of obesity or cancer.
Scientists from Duke University in the US 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. The supplements also 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 Dr Randy Jirtle, senior investigator of the study, published in today's issue of Molecular and Cellular Biology.
"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."
In experiments, pregnant mice that received 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.
This is called 'DNA methylation', and it could potentially affect dozens of other genes that make humans and animals susceptible to cancer, obesity, diabetes, and even autism, said Jirtle.
"Our study demonstrates how early environmental factors can alter gene expression without mutating the gene itself," said Dr Rob Waterland, a research fellow in the Jirtle laboratory and lead author of the study. "The implications for humans are huge because 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. The methyl group silences the gene or reduces its expression inside a given cell, but does not actually change it. 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 four-unit genetic code.
In the study, researchers noted that the methylation occurred early during gestation, shown 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.
Humans and other animals are susceptible to epigenetic changes because of an evolutionary trait in which "junk" remnants of viral infections, called "transposons," inserted themselves randomly within the human and animal genomes. If the transposons have inserted themselves in or near a functional gene, the gene can be inadvertently methylated, too, thereby reducing its expression.
The scientists demonstrated that such inadvertent methylation occurred at the Agouti gene when the mice were fed the nutrients. The four nutrients encourage methylation because they possess chemicals that donate methyl groups within cells. Thus, they are primed to methylate susceptible sites in the genome. In fact, more than 40 per cent of the human genome is comprised of transposons that are likely to be methylated, so any genes positioned near them could be at risk for inadvertent methylation.
"We used a model system to test the hypothesis that early nutrition can affect phenotype through methylation changes," said Jirtle. "Our data confirmed the hypothesis and demonstrated that seemingly innocuous nutrients could have unintended effects, either negative or positive, on our genetic expression."
For example, methylation that occurs near or within a tumour suppressor gene can silence its anti-cancer activity, said Jirtle. Also they do not know which of the four nutrients caused methylation of the Agouti gene, revealing the uncertainty of nutrition's epigenetic effects on cells, said Jirtle. Folic acid is a staple of prenatal vitamins, used to prevent neural tube defects like spina bifida, but excess folic acid could methylate a gene and silence its expression in a detrimental manner, as well.
Methylating a single gene can also have multiple effects. For example, as well as changing 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.
The researchers stressed the importance of understanding the molecular effects of nutrition on cells, not just the outward manifestations of it.
"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. "Nutritional epigenetics could, for example, explain the differences between genetically identical twins, or the disparities in the incidence of stroke between the South and the North. The possibilities are endless."