October 08, 2003
Nutrients Change Embryonic DNA Methylation, Risk Of Disease

Fairly small changes in nutrient levels caused dramatic developmental changes in mice.

In a study of nutrition's effects on development, the scientists showed they could change the coat color 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.

Results of the study are published in and featured on the cover of the Aug. 1, 2003, issue of Molecular and Cellular Biology.

"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, Ph.D., professor of radiation oncology at Duke and 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."

In the Duke experiments, 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.

That choice of nutrients was not just a wild guess on the part of the researchers. Those nutrients are all known to serve as methyl donors in a number of metabolic pathways. Methylation is done to many other compounds besides DNA and most of the pathways that use these nutrients to methylate do so to serve other purposes such as changing hormones into other kinds of hormones (and in some cases the methyls are chopped off rather than added).

What is interesting to note about folic acid's role is that the US government and other governments have authorized the addition of folic acid to grain foods in order to lower the risk of spina bifida. At the same time, lots of people are trying to get more folic acid in their diets in order to reduce the risk of Alzheimer's, heart disease (on the theory that folic acid will catalyze pathways that will lower blood homocysteine and, by doing so, reduce the rate of atherosclerotic build-up), and other diseases whose risks may be lower if one gets more folic acid in one's diet. So if increased folic acid will cause changes in human development by increasing DNA methylation we are going to eventually see some unexpected changes in health between generations. Whether those changes will be for good or ill or, perhaps, a mixture of both remains to be seen. We really can only guess at this point. If this worries you keep in mind that industrialization has certainly caused large changes in the nutritional composition of our diets already. Folic acid fortification of food is just one of many changes in our diets and environments that are probably changing human development in all sorts of ways which have not yet been identified.

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 color change. Yet the Agouti gene itself remained unchanged.

Just how the babies' coat colors changed without their Agouti gene being altered is the most exciting part of their research, said Jirtle. The mechanism that enabled this permanent color 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.

This ability to change the expression of genes without actually changing their primary sequence is very important. Some genetic engineering in the future aimed at changing offspring will likely be done by causing epigenetic changes rather than changes in the primary DNA sequence. What will be interesting to see is whether more precise methods of controlling methylation can be developed. The use of diet to increase the amount of methylating nutrients that a fetus is exposed to is an intervention that has rather broad effects. Some of the resulting methylations may have desired effects but other methylations near other genes might cause effects that are harmful.

"Our study demonstrates how early environmental factors can alter gene expression without mutating the gene itself," said Rob Waterland, Ph.D., 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. 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 four-unit 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. In fact, data gathered by Swedish researcher Gunnar Kaati and colleagues indicates just such a multi-generational effect. In that study of nutrition in the late 1800s, boys who reached adolescence (when sperm are reaching maturity) during years of bountiful crop yield produced a lineage of grandchildren with a significantly higher rate of diabetes. No cause-and-effect link was established, but Jirtle suspects epigenetic alterations could underlie this observation.

What is frustrating about a report like this is that it is a reminder that some environmental factors that we can easily manipulate (e.g. the amount of folic acid in the diet at each stage in development) are probably creating a large variety of effects which we simply don't know enough about to know that we should want to manipulate relevant the controllable factors. Some of us might have gotten lucky because our mothers happened to eat more folic acid rich lentils and greens at one stage of development when it would have helped us in some way and perhaps at less of them at some other stage where the effect of more methylation activity might have been more harmful. But others happened to have gotten dosed with methylating nutrients at other stages of development and therefore got stuck with a worse result in terms of predisposition for obesity, diabetes, cancer, hair texture, or who knows what else.

"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 tumor suppressor gene can silence its anti-cancer activity, said Jirtle. Similarly, methylation may have silenced genes other than Agouti in the present study genes that weren't analyzed for potential methylation. And, the scientists do not know which of the four nutrients alone or in combination caused methylation of the Agouti gene.

Herein lies 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. Yet excess folic acid could methylate a gene and silence its expression in a detrimental manner, as well. The data simply don't exist to show each nutrient's cellular effects.

Moreover, methylating a single gene can have multiple effects. For example, the Agouti gene regulates more than just coat color. 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.

Not only can increased methylation of a single gene have multiple effects but increased methylation caused by nutritional supplementation would likely cause increased methylation on other genes and thereby have yet more other effects. But if that is not complicated enough already note that in this experiment the nutrients caused mice that would otherwise be obese to be skinny instead. Well, not all mice are genetically predisposed toward obesity. The effects of supplementation using these same nutrients may cause different effects in other strains of mice. For instance, a gene that is not expressed much in this mouse strain might be expressed more in another mouse strain but folic acid might down-regulate it in the other mouse strain while not causing the down-regulation effect in this mouse strain.

The Duke researchers say much more work of this sort will be forthcoming from many labs.

"One of the things we need to do now is refine this model and see how generalizable it is," Waterland said. He noted that he and Jirtle still don't know which one or combination of the nutritional supplements created the changes in the experimental mice. They also want to know if other genes might be involved, and if the supplements caused any negative effects.

"You're going to see more of this kind of work," Jirtle said, "not just from our group, but from all over."

Variations in nutrient levels are just one cause of changes in methylation patterns that can produce enduring effects. Environmental stimuli can cause changes in methylation patterns that cause changes in personality and behavior.

Methylation that occurs after birth may also shape such behavioral traits as fearfulness and confidence, said Dr. Michael Meaney, a professor of medicine and the director of the program for the study of behavior, genes and environment at McGill University in Montreal.

For reasons that are not well understood, methylation patterns are absent from very specific regions of the rat genome before birth. Twelve hours after rats are born, a new methylation pattern is formed. The mother rat then starts licking her pups. The first week is a critical period, Dr. Meaney said. Pups that are licked show decreased methylation patterns in an area of the brain that helps them handle stress. Faced with challenges later in life, they tend to be more confident and less fearful.

For more on Dr. Meaney's work see here and here.

While back in the 1950s Dr. Spock confidently held forth on what were the best child-raising practices he really didn't know what he was talking about. A half century later there are still lots of ways in which child-rearing practices might be having unrecognized subtle effects upon human offspring. For instance, there might be some way of handling babies in the first few months of life which, analogous to the licking behavior of mouse mothers, will increase or decrease the risk of anxiety or depression because the practice changes methylation patterns in the brain. As of yet we just don't know what these ways are.

Fortunately just as there was a large effort to sequence the human genome and there is now a large effort to map all the genetic variations there is also a project to map all the places where methylation happens on the human genome and what the effects are of methylation on all the sites where it happens.

The Human Epigenome Project follows the completion of the Human Genome Project and aims to map the way methyl groups are added to DNA across the entire human genome. These "epigenetic" changes are believed to turn genes on and off. Scientists at the Wellcome Trust Sanger Institute in Cambridge, UK, and Epigenomics, a Berlin-based company, are leading the project.

Update: If, as I expect, many nutritional and other factors are discovered that influence human development in enduring ways the result will be a wide embrace of much more management of maternal diet and environment and of the environment of newborns. The speculative advice of the pop psych baby books of the past and present will be replaced with much more precise and accurate advice derived from a scientifically rigorous model of human development. Genetic profiles of mothers and embryos will be used to develop highly customized instructions for diet and environment in order to increase the odds that some parentally chosen desired ideal epigenetic programming of each baby will be achieved. Therefore the development of much greater knowledge of human development may well result in a more regimented and demanding approach to having and caring for babies. While this may make having a baby an even greater ordeal than it is already it should be expected that pharmaceuticals will eventually be developed that will be able to ensure a particular epigenetic outcome with less work on the part of mothers and fathers to manage the pre- and post-natal environment.

Share |      Randall Parker, 2003 October 08 01:16 AM  Biotech Advance Rates


Comments
Bob Badour said at October 8, 2003 5:54 AM:

Hmmmm... might partially explain the epidemic of obesity in North America.

Nancy Lebovitz said at October 8, 2003 8:49 AM:

Here's a practice that might have long-term side effects: expecting babies to sleep by themselves. It's certainly not something that was standard or safe for most of human evolution, and it might be contributing a lot of background stress.

Randall Parker said at October 8, 2003 11:00 AM:

Nancy, You could be right. Plus, there is the amount of time that the baby spends in close contact with mom during the waking hours. That time has almost certainly declined as women have been using formula, baby-sitters and for other reasons spending less time with the baby right up against their bodies.

It also might be the case that breast-feeding delivers a hormone that affects neural development. Plus, there is the known importance of omega-3 fatty acids and for many years formulas had less omega-3's than breast milk. Plus, dietary changes have probably caused changes in the amount of omega-3's in breast milk.

dipali joshi said at August 24, 2005 2:21 AM:

this sounds like a very prospective way of designing babies.....and its not even invasive in any way..natural 100%

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