More choline during pregnancy and nursing could provide lasting cognitive and emotional benefits to individuals with Down syndrome and protect against neurodegenerative conditions such as Alzheimer's disease, suggests a new Cornell study of mice.

The findings, published June 2 in Behavioral Neuroscience, could help lead to increasing the maternal dietary recommendations for choline (currently 450 milligrams a day during pregnancy, 550 milligrams for lactation), a nutrient found in egg yolks, liver, nuts and such vegetables as broccoli and cauliflower.

"We found that supplementing the maternal diet with additional choline resulted in dramatic improvements in attention and some normalization of emotion regulation in a mouse model of Down syndrome," said lead author Barbara Strupp, professor of nutritional sciences and of psychology. The researchers also found evidence for "subtle, but statistically significant, improvement in learning ability in the non-Down syndrome littermates."

In addition to mental retardation, Down syndrome individuals often experience dementia in middle age as a result of brain neuron atrophy similar to that suffered by people with Alzheimer's disease. Strupp noted that the improved mental abilities found in the Down syndrome mice following maternal choline supplements could indicate protection from such neurodegeneration "in the population at large."

Strupp and her co-authors tested Down syndrome model mice born from mothers fed a normal diet and those given choline supplements during their three-week pregnancy and three-week lactation period, as well as normal mice born from mothers with and without additional choline. The choline-supplemented mothers received approximately 4.5 times more choline (roughly comparable to levels at the higher range of human intake) than unsupplemented mothers.

In addition to dramatic improvements in attention, the researchers found that the unsupplemented Down syndrome model mice became more agitated after a mistake than normal mice, jumping repeatedly and taking longer to initiate the next trial, whereas the choline-supplemented Down syndrome model mice showed partial improvement in these areas.

"I'm impressed by the magnitude of the cognitive benefits seen in the Down syndrome model mice," Strupp said. "Moreover, these are clearly lasting cognitive improvements, seen many months after the period of choline supplementation."

Strupp noted that the results are consistent with studies by other researchers that found increased maternal choline intake improves offspring cognitive abilities in rats. However, this is the first study to evaluate the effects of maternal choline supplementation in a rodent model of downs syndrome.  This is also one of the few studies that has evaluated offspring attentional function and effects in mice, rather than rats, Strupp noted.

Previous studies of humans and laboratory animals have shown that supplementing the diets of adults with choline has proven to be largely ineffective in improving cognition. "Although the precise mechanism is unknown, these lasting beneficial effects of choline observed in the present study are likely to be limited to increased intake during very early development," Strupp said.

A newborn's risk for brain and spinal-cord defects rises if the mother has low blood levels of the nutrient choline during pregnancy, researchers at the Stanford University School of Medicine have discovered.

The scientists used a collection of 180,000 blood samples from pregnant California women to look for risk factors for two neural tube birth defects: anencephaly, a lethal condition in which the brain and skull do not develop, and spina bifida, a spinal-cord malformation that causes paralysis and lifelong disability. Neural tube defects have become less common since the 1996 decision to fortify the U.S. food supply with folic acid, a B-vitamin shown to prevent the defects, but they have not disappeared.

"Families whose infants die or suffer permanent disability from NTDs still feel the burden of these defects," said Gary Shaw, DrPH, professor of neonatology and primary author of the new research, which will appear Aug. 14 in Epidemiology.

About 500 pregnancies per year are affected by neural tube defects in California alone, noted Shaw. "We're keen on understanding what risk factors explain the continued disease."

Shaw's study targeted a group of nutrients suspected to promote brain and spinal-cord development. In early pregnancy, a sealed tube forms along the embryo's back that later grows into the brain and spinal cord. Neural tube defects occur if the tube does not seal correctly. Based on prior research on folic acid, scientists believe that development of the neural tube may depend on a specific biochemical pathway that requires several vitamins and essential nutrients to operate properly. Shaw's team measured blood levels of 13 of these nutrients in two groups of women who participated in California's prenatal birth-defect screening program.

From 180,000 pregnant women screened between 2003 and 2005, the researchers identified 80 whose pregnancies were affected by neural tube defects. Their blood samples were compared to 409 samples randomly selected from among the women whose infants had no structural birth defects.

Choline, an essential nutrient found in egg yolks, soy, wheat germ and meats, was the only nutrient measured whose blood levels were linked to risk of neural tube defects.

"As choline levels went up, risk went down," Shaw said. Risk for neural tube defects was 2.4 times higher in women with the lowest blood choline levels compared to women with average blood choline levels. The highest blood choline levels were associated with the lowest risk. A previous study by Shaw's group showed that consumption of choline-rich foods was associated with lower risk for neural tube defects, but this is the first study to evaluate blood levels of choline and NTD risk.

Shaw's work provides a promising target for future clinical trials on neural tube defect prevention, said Louanne Hudgins, MD, division chief of medical genetics at Lucile Packard Children's Hospital, who did not participate in the study. Hudgins, who is also a professor of pediatric genetics at the medical school, regularly counsels families facing prenatal diagnoses of neural tube defects. "You can't change an individual's genetic predisposition to these defects. But nutrition components to NTD risk are ripe for therapy," she said.

Shaw cautioned that the blood samples tested were obtained between the 15th and 18th week of pregnancy, well after formation of the neural tube, which seals around the sixth week of pregnancy. Future research will be needed to examine blood choline levels in early pregnancy, he said. Researchers also need to test whether choline supplements given in early pregnancy reduce the rates of neural tube defects. Right now, prenatal multivitamins contain little or no choline.

For women who want to become pregnant, "the best source for choline is still eating a variety of foods," Shaw concluded. Women of reproductive age should also follow U.S. Public Health Service recommendations to take a multivitamin containing other nutrients previously shown to promote healthy pregnancies, he said.

Permanent improvement in deficient sensory inhibition in DBA/2 mice with increased perinatal choline.

Perinatal choline deficiency produces abnormal sensory inhibition in Sprague-Dawley rats.

Experiment of nature' examines how mother's diet may impact on child's health

Could our mother's diet at the time we are conceived set the course for our future health? This intriguing question is at the heart of a new study based on an "experiment of nature" being conducted by Wellcome Trust-funded researchers.

We inherit our DNA the genetic blueprint that determines our make-up from our parents: 50% of our DNA from our mothers and 50% from our fathers. Apart from the occasional mutation, deletion or duplication of information, this DNA remains unchanged between generations.

The environment, for example our diet, whether we smoke, and the toxins that we encounter in our daily life, can cause changes in how our genes are expressed in other words, how they function and these changes can be inherited, even when the DNA sequence itself does not change. These so-called "epigenetic" effects can occur through a process known as DNA methylation, where methyl caps bind to our DNA and act like dimmer switches on our genes.

Now, Dr Branwen Hennig and colleagues from the Medical Research Council (MRC) International Nutrition Group based at the London School of Hygiene and Tropical Medicine have been awarded 360,000 from the Wellcome Trust to look at whether a mother's diet during pregnancy can influence these epigenetic effects.

The study will be conducted at the MRC Laboratories in Keneba, The Gambia, where the seasonal variability of food provides the ideal environment to conduct an "experiment of nature".

"During the 'hungry season' people eat mainly what they have in store, such as cereals and dried food," explains Ms Paula Dominguez-Salas, who will conduct the fieldwork in The Gambia. "They are working in the fields and have a very high energy expenditure, but their intake is very low. The 'harvest season' is the other way round and food, including fresh foods, is in relatively plentiful supply."

The researchers will measure the diets of women in early pregnancy for nutrients which affect methylation, such as folate and choline, and some B vitamins which are essential co-factors in methylation. They will compare these to levels of the nutrients in the women's blood and once the children have been born, the researchers will measure methylation patterns of the babies' DNA. This will help the researchers assess whether there is a correlation between the mother's diet and her nutritional status, and whether there are differences in methylation patterns in babies conceived during the harvest or hungry seasons.

If a mother's diet does affect her offspring's methylation patterns, this could prove very important as epigenetic changes mediated by DNA methylation are likely to have long term effects on the health and physical characteristics of offspring. Animal studies have shown that supplementing the diet of pregnant mice can lead to very marked differences in their offspring with mice fed a folate-depleted diet producing litter with different coat colour or "kinked" tails compared to those fed a diet rich in folate.

"Alterations in DNA methylation are thought to increase the risk of a child developing chronic conditions later in life, such as cardiovascular disease, cancers and type II diabetes," says Dr Hennig. "We think these epigenetic changes are established very early on in the womb."

This will be the first time that the effects of a mother's diet on epigenetic alterations of her children will be studied so extensively. A study published recently in the Proceedings of the National Academy of Sciences looked at the effect of wartime blockades in the Netherlands on the nutritional intake of mothers and whether this affected their children's expression of the IGF2 gene, which is involved in growth, as adults. It found that the IGF2 gene had 5 per cent fewer methyl caps in "famine babies" than in their siblings born outside this period. However, the study by Dr Hennig and colleagues will enable the researchers to accurately measure maternal nutritional intake and compare this to methylation patterns in their children.

The study has been welcomed by Dr Alan Schafer, Head of Molecular and Physiological Sciences at the Wellcome Trust.

"This is a very interesting and exciting area of research," says Dr Schafer. "Finding a link between these women's diet and epigenetic changes could ultimately have important implications for our understanding of long term health effects and advice on healthy eating."

Source; Welcome Trust

"Dr. Zeisel pointed out that choline is very important for the fetal brain, and can be obtained as a supplement as phosphatidyl choline [obtained via Lecithin].  2-4 eggs per day provide enough choline during pregnancy.  The current daily value is 450 mg, but it would be useful to set the level at 850 mg.   It is like fish oil, having lifelong effect on an infant's early brain development. "

"Evidence is growing that optimal dietary intake of folate and choline (both involved in one-carbon transfer or methylation) is important for successful completion of fetal development. Significant portions of the population are eating diets low in one or both of these nutrients.

Folates are important for normal neural tube closure in early gestation, and the efficacy of diet fortification with folic acid in reducing the incidence of neural tube defects is a major success story for public health nutrition. Similarly, maternal dietary choline is important for normal neural tube closure in the fetus and, later in gestation, for neurogenesis in the fetal hippocampus, with effects on memory that persist in adult offspring; higher choline intake is associated with enhanced memory performance."

"during perinatal development in which specific nutrients are required for optimal development, and there is growing evidence that optimal dietary intake of these nutrients, which include iodine, docosahexaenoic acid, choline, and folate, is important. ... For some of the nutrients discussed, such as iodine and folate, the effects in humans are abundantly clear; for others, animal data are the most convincing. More human studies need to be conducted."

"It is clear that the dietary manipulation of methyl donors (either deficiency or supplementation) can have a profound effect on reproductive outcome through epigenetic mechanisms. For this reason, it is important that expert panels carefully consider recommendations for dietary intake of methyl donors during pregnancy."

Importance of methyl donors during reproduction (Steven Zeisel), American Journal of Clinical Nutrition

Is maternal diet supplementation beneficial? Optimal development of infant depends on mother's diet

(Steven Zeisel), American Journal of Clinical Nutrition

Eating eggs when pregnant Reduces Risk of Aggressive breast cancer in offspring

New research shows that the 'genetic impact' of a pregnant woman's diet has a profound effect on her child

A stunning discovery based on epigenetics (the inheritance of propensities acquired in the womb) reveals that consuming choline--a nutrient found in eggs and other foods--during pregnancy may significantly affect breast cancer outcomes for a mother's offspring. This finding by a team of biologists at Boston University is the first to link choline consumption during pregnancy to breast cancer. It also is the first to identify possible choline-related genetic changes that affect breast cancer survival rates.

"We've known for a long time that some agents taken by pregnant women, such as diethylstibesterol, have adverse consequences for their daughters," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "But there's an upside. The emerging science of epigenetics has yielded a breakthrough. For the first time, we've learned that we might be able to prevent breast cancer as early as a mother's pregnancy."

The researchers made the discovery in rats by studying females whose mothers were fed varying amounts of choline during pregnancy. Different groups of pregnant rats received diets containing standard amounts of choline, no choline at all, or extra choline. Then the researchers treated the female offspring with a chemical that causes cancer of the mammary gland (breast cancer). Although animals in all groups developed mammary cancer, the daughters of mothers that had received extra choline during pregnancy had slow growing tumors while daughters of mothers that had no choline during pregnancy had fast growing tumors.

"Our study provides additional support for the notion that choline is an important nutrient that has to be considered when dietary guidelines are developed," said Krzysztof Blusztajn, Ph.D., Professor of Pathology at Boston University and the study's senior researcher. "We hope it will be possible to develop nutritional guidelines for pregnant women that ensure the good health of their offspring well into old age."

The researchers also found multiple genetic and molecular changes in the rats' tumors that correlated with survival outcomes. For example, the slow growing tumors in rats had a genetic pattern similar to those seen in breast cancers of women who are considered to have a good prognosis. The fast growing tumors in mice had a pattern of genetic changes similar to those seen in women with a more aggressive disease. The researchers also found evidence that these genetic changes may result from the way that choline affects modifications of the DNA within the mammary gland of fetuses as they develop in the womb.

The National Cancer Institute estimates that there will be more than 184,000 new cases of breast cancer in 2008 and more than 40,000 deaths. Treatments for women suffering from breat cancer range from hormone therapy to surgery.

Research Source:

"Our findings suggest that a mother's diet that alters DNA methylation can affect the development of the fetus's immune system, predisposing it to allergic airway disease," said David Schwartz, MD, senior author on the paper and Professor of Medicine at National Jewish Health. "It also suggests the dramatic increase in asthma during the past two decades may be related in part to recent changes in dietary supplementation among women of childbearing age."

The prevalence of asthma has nearly doubled in the past 25 years. Asthma currently affects about 11 percent of the US population and accounts for $9.4 billion in direct healthcare costs. Although both genes and environment are believed to play a role in the development of asthma, scientists have been unable to definitively identify specific causes of the disease or explain the rise in prevalence.

Epigenetics is the study of gene regulation. Environmental exposures can lead to modification of methyl groups (CH3) binding to certain DNA molecules, which can result in modified expression of specific genes. A variety of environmental factors, including diet, tobacco smoke, and medications, can modify methyl groups binding to DNA, particularly during periods of vulnerability. Although no changes occur in the genetic code, epigenetic effects can be passed to offspring. Emerging research has indicated that epigenetic mechanisms can affect the development of the immune system, skewing it either toward or away from a predisposition to allergies.

The research team decided to examine the potential role of epigenetics in the development of allergic asthma. They fed pregnant mice diets either high or low in methyl donors. In addition to folic acid, the high methyl-donor diets additionally contained higher levels of L-methionine, choline, and genistein.

The male offspring also transmitted a higher predisposition to allergic airway disease to their progeny. In contrast, mice exposed to high-methyl-donor diets during lactation or adulthood showed no increased propensity to allergic sensitization.

"There seems to be a crucial stage, during development in utero, when a young mouse is susceptible to epigenetic changes that can alter its immune system," said co-author John W. Hollingsworth, Assistant Professor of Medicine at Duke University School of Medicine. "These epigenetic changes may partially explain why it has been so difficult to definitively identify genes that contribute to asthma risk; the effect of genetic variations can be masked or further complicated by epigenetic changes."

When the researchers analyzed the genomes of the mice, they identified 82 genes that were significantly more methylated in high-methyl-diet (HMD) mice. The 10 most methylated genes were biologically plausible causes of asthma. These genes were transcription factors, which control the expression of many genes, and genes associated with cellular migration and allergic airway disease. The highly methylated genes were expressed at lower levels than less-methylated genes in mice receiving the low-methyl-donor diets.

The current research suggests too much folic acid (and other dietary supplements) during pregnancy may be related to an increased risk of allergies and asthma, and may even play a role in the dramatic increase in asthma prevalence during the past two decades. The U.S. Public Health service recommended in 1992 that all women of childbearing age consume 400 micrograms of folic acid daily to reduce their risk of birth defects of the spine and brain. In 1996 the U.S. Food and Drug Administration required that folic acid be added to specific flour, breads and other grains to prevent birth defects. Research has suggested that these measures have helped reduce birth defects.

Given the important role folic acid supplementation has played in prevention of birth defects, Drs. Schwartz and Hollingsworth do not advise any changes in folic acid supplementation, but do believe the issue is worth further investigation.

A new research study done at MIT suggests that a combination of choline, omega-3 fatty acids with the uridine improved memory and learning in gerbils, and may have benefits for Alzheimer patients.

Animals fed the nutrient mix performed better in maze tests than animals not fed the combination, a result attributed to improved cognitive function, according to results published in the Federation of American Societies of Experimental Biology (FASEB) journal.

Researchers from MIT are now taking the research a step further and have are exploring the potential of a beverage-based prevention for Alzheimer's and other brain diseases.

"It may be possible to use this [combination] to partially restore brain function in people with diseases that decrease the number of brain neurons, including, for example, Alzheimer's disease, Parkinson's, strokes and brain injuries. Of course, such speculations have to be tested in double-blind, placebo-controlled clinical trials," said senior author Richard Wurtman.

Trials are reportedly underway in Europe, and preliminary results have been submitted to the Alzheimer's Association International Conference on Alzheimer's Disease, to be held in Chicago at the end of this month.

Wurtman and co-workers supplemented the diets of gerbils with uridine (in its monophosphate form, 0.5 per cent) and choline (0.1 per cent), and docosahexaenoic acid (DHA, 300 mg/kg/day) for four weeks.

DHA is an omega-3 fatty acids obtained predominantly from marine sources. Choline is found in meats, nuts and eggs, and can also be made by the body. Uridine, on the other hand, is contained in breast milk and synthesized by the body - there seems to be some debate as to whether it is available in foods - I've seen some sources that suggest that uridine is found in beets, other sources have said its not available in any food products.

At the end of the study, significant increases in phospholipid levels in the brain were observed when the compounds were given together, while administration of only DHA or UMP or UMP plus choline produced smaller increases.