Fw: [Autism_iron] methylation and mother's diet

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Subject: [Autism_iron] methylation and mother's diet

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http://www.nytimes.com/2003/10/07/science/...GENE.html?8hpib

A Pregnant Mother's Diet May Turn the Genes Around

By SANDRA BLAKESLEE

Published: October 7, 2003

With the help of some fat yellow mice, scientists have discovered exactly

how a mother's diet can permanently alter the functioning of genes in her

offspring without changing the genes themselves.

Duke University

Dietary supplements given to pregnant mice shift their offspring's coat

color. These mice are genetically identical.

The unusual strain of mouse carries a kind of trigger near the gene that

determines not only the color of its coat but also its predisposition to

obesity, diabetes and cancer. When pregnant mice were fed extra vitamins and

supplements, the supplements interacted with the trigger in the fetal mice and

shut down the gene. As a result, obese yellow mothers gave birth to standard

brown baby mice that grew up lean and healthy.

Scientists have long known that what pregnant mothers eat - whether they

are mice, fruit flies or humans - can profoundly affect the susceptibility of

their offspring to disease. But until now they have not understood why, said Dr.

Randy Jirtle, a professor of radiation oncology at Duke and senior investigator

of the study, which was reported in the Aug. 1 issue of Molecular and Cellular

Biology.

The research is a milestone in the relatively new science of epigenetics,

the study of how environmental factors like diet, stress and maternal nutrition

can change gene function without altering the DNA sequence in any way.

Such factors have been shown to play a role in cancer, stroke, diabetes,

schizophrenia, manic depression and other diseases as well as in shaping

behavioral traits in offspring.

Most geneticists are focusing on sequences of genes in trying to

understand which gene goes with which illness or behavior, said Dr.

Insel, director of the National Institute of Mental Health. " But these

epigenetic effects could turn out to be much more important. The field is

revolutionary, " he said, " and humbling. "

Epigenetics may indeed hold answers to many mysteries that classical

genetic approaches have been unable to solve, said Dr. Arturas Petronis, an

associate professor of psychiatry at the Center for Addiction and Mental Health

at the University of Toronto.

For example, why does one identical twin develop schizophrenia and not the

other? Why do certain disease genes seem to affect or " penetrate " some people

more than others? Why do complex diseases like autism turn up in more boys than

girls?

For answers, epigeneticists are looking at biological mechanisms other

than mutation that affect how genes function. One, called methylation, acts like

a gas pedal or brake. It can turn gene expression up or down, on or off,

depending on how much of it is around and what part of the genetic machinery it

affects.

During methylation, a quartet of atoms called a methyl group attaches to a

gene at a specific point and induces changes in the way the gene is expressed.

The process often inactivates genes not needed by a cell. The genes on one of

the two X chromosomes in each female cell are silenced by methylation.

Methyl groups and other small molecules may sometimes attach to certain

spots on chromosomes, helping to relax tightly coiled strands of DNA so that

genes can be expressed. Sometimes the coils are made tighter so that active

genes are inactivated.

Methyl groups also inactivate remnants of past viral infections, called

transposons. Forty percent of the human genome is made up of parasitic

transposons.

Finally, methyl groups play a critical role in controlling genes involved

in prenatal and postnatal development, including some 80 genes inherited from

only one parent. Because these so-called imprinted genes must be methylated to

function, they are vulnerable to diet and other environmental factors.

When a sperm and egg meet to form an embryo, each has a different pattern

of methylated genes. The patterns are not passed on as genes are, but in a

chemical battle of the sexes some of the egg and sperm patterns do seem to be

inherited. In general, the egg seems to have the upper hand.

" We're compounds, mosaics of epigenetic patterns and gene sequences, " said

Dr. Arthur Beaudet, chairman of the molecular and human genetics department at

Baylor College of Medicine in Houston. While DNA sequences are commonly compared

to a text of written letters, he said, epigenetics is like the formatting in a

word processing program.

Though the primary letters do not vary, the font can be large or small,

Times Roman or Arial, italicized, bold, upper case, lower case, underlined or

shadowed. They can be any color of the rainbow. Methylation is nature's way of

allowing environmental factors to tweak gene expression without making permanent

mutations, Dr. Jirtle said.

Fleeting exposure to anything that influences methylation patterns during

development can change the animal or person for a lifetime. Methyl groups are

entirely derived from the foods people eat. And the effect may be good or bad.

Maternal diet during pregnancy is consequently very important, but in ways that

are not yet fully understood.

For his experiment, Dr. Jirtle chose a mouse that happens to have a

transposon right next to the gene that codes for coat color. The transposon

induces the gene to overproduce a protein that turns the mice pure yellow or

mottled yellow and brown. The protein also blocks a feeding control center in

the brain. Yellow mice therefore overeat and tend to develop diabetes and

cancer.

To see if extra methylation would affect the mice, the researchers fed the

animals a rich supply of methyl groups in supplements of vitamin B12, folic

acid, choline and betaine from sugar beets just before they got pregnant and

through the time of weaning their pups. The methyl groups silenced the

transposon, Dr. Jirtle said, which in turn affected the adjacent coat color

gene. The babies, born a normal brownish color, had an inherited predisposition

to obesity, diabetes and cancer negated by maternal diet.

Unfortunately the scientists do not know which nutrient or combination of

nutrients silence the genes, but noted that it did not take much. The animals

were fed only three times as much of the supplements as found in a normal diet.

" If you looked at the mouse as a black box, you could say that adding

these methyl-rich supplements to our diets might reduce our risk of obesity and

cancer, " Dr. Jirtle said. But, he added, there is strong reason for caution.

The positions of transposons in the human genome are completely different

from the mouse pattern. Good maps of transposons in the human genome need to be

made, he said. For that reason, it may be time to reassess the way the American

diet is fortified with supplements, said Dr. Rob Waterland, a research fellow in

Dr. Jirtle's lab and an expert on nutrition and epigenetics.

More than a decade ago, for example, epidemiological studies showed that

some women who ate diets low in folic acid ran a higher risk of having babies

with abnormalities in the spinal cord and brain, called neural tube defects.

To reduce this risk, folic acid was added to grains eaten by all

Americans, and the incidence of neural tube defects fell substantially. But

while there is no evidence that extra folic acid is harmful to the millions of

people who eat fortified grains regularly, Dr. Waterland said, there is also no

evidence that it is innocuous.

The worry is that excess folic acid may play a role in disorders like

obesity or autism, which are on the rise, he said. Researchers are just

beginning to study the question.

Epidemiological evidence shows that undernutrition and overnutrition in

critical stages of development can lead to health problems in second and third

generations, Dr. Waterland said.

A Dutch famine near the end of World War II led to an increased incidence

of schizophrenia in adults who had been food-deprived during the first trimester

of their mothers' pregnancy. Malnourishment among pregnant women in the South

during the Civil War and the Depression has been proposed as an explanation for

the high incidence of stroke among subsequent generations.

And the modern American diet, so full of fats and sugars, could be

exerting epigenetic effects on future generations, positive or negative.

Abnormal methylation patterns are a hallmark of most cancers, including colon,

lung, prostate and breast cancer, said Dr. Laird, an associate professor

of biochemistry and molecular biology at the University of Southern California

School of Medicine.

The anticancer properties attributed to many foods can be linked to

nutrients, he said, as well as to the distinct methylation patterns of people

who eat those foods. A number of drugs that inhibit methylation are now being

tested as cancer treatments. Psychiatrists are also getting interested in the

role of epigenetic factors in diseases like schizophrenia, Dr. Petronis said.

Methylation that occurs after birth may also shape such behavioral traits

as fearfulness and confidence, said Dr. 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.

" We think licking affects a methylation enzyme that is ready and waiting

for mother to start licking, " Dr. Meaney said. In perilous times, mothers may be

able to set the stress reactivity of their offspring by licking less. When there

are fewer dangers around, the mothers may lick more.

--------------------

Lazarus Long

" The world we know is as much one of creation as it is of discovery. "

[Guest guest]

Dr Deth did a study on how thimerosal interferes with folate-

dependent methylation which can cause neurodevelopmental disorders.

(A LOT OF DIFFRENT DISORDERS)

studies showed that low methylation is associated with more

breakage in DNA strands. This is also the cause of disease in old

age.

Mutagens, such as chemicals or radiation, damage DNA which if not

repaired by DNA repair enzymes will lead to mutations.

DNA methylation is a chemical modification of the DNA molecule

itself; it is carried out by an enzyme called DNA methyltransferase.

Methylation can directly switch off gene expression by preventing

transcription factors binding to promoters.

Usually DNA damages (such as from uv light) are corrected by repair

enzymes. When the repair mechanism breaks down, it causes a

progressive process in ageing, in many age-related diseases like

cancer and in genetic diseases such as Down´s syndrome, cystic

fibrosis and Werner´s syndrome. People with DNA repair disorders

often have broken chromosomes, following exposure to ionizing

radiation or chemicals that affect cell division.

Chemicals such as mercury intefere with Methylation, the repair

mechanism. Older people have a lot more toxins built up in thier

bodies from years of exposure, This is what causes DNA Damage and

Eventually Death in old age.

Donna

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