Nine articles about epigenetics from the popular press, in chronological order.

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Wall Street Journal

August 15, 2003

Chubby Blonde? Slim and Dark?

Lab Mice Take After Mom's Diet

by Sharon Begley

The baby mice looked as different as night and day.

Those in one litter were dirty blondes, while those in the other were, well, mousy brown. Yet the mice's genes for coat color were identical, down to the last A, T, C and G that make up the twisting strands of DNA.

The reason some animals were yellow and some were brown lay deep in their fetal past, biologists at Duke University Medical Center, Durham, N.C., reported this month: Some of the mothers consumed supplements high in very simple molecular compounds that zip around the genome turning off genes. One silenced gene was for yellow fur; when it is turned off, the mouse's fur color defaults to brown. For the mice, it wasn't just that "you are what you eat," but that you are what your mother ate, too.

The ink on the final draft of the complete human genome sequence is hardly dry, but scientists are seeing more and more instances in which the sequence of those celebrated A's, T's, C's and G's constituting the genome is only part of the story.

Biologists have long known that having a particular gene is no guarantee you will express the associated trait, any more than having a collection of CDs will fill your home with music. Like CDs, genes are silent unless they are activated. Because activating and silencing doesn't alter the sequence of the gene, such changes are called epigenetic.

"Epigenetics is to genetics as the dark matter in the universe is to the stars; we know it's important, but it's difficult to see," says geneticist Andrew Feinberg of Johns Hopkins University School of Medicine, Baltimore. "What we're thinking now is that, in addition to genetic variation, there may be epigenetic variation that is very important in human disease."

Epigenetic variation may explain such long-running mysteries as why identical twins are, in many ways, no such thing, including whether they have such supposedly genetic diseases as schizophrenia and cancer. Epigenetics may also help explain how the seeds of many adult diseases may be planted during fetal life. Studies suggest that the nutrition a fetus receives -- as indicated by birth weight -- might influence the risk of adult-onset diabetes, heart disease, hypertension and some cancers. The basis for such "fetal programming" has been largely an enigma, but epigenetics may be key.

There is no doubt that, in the case of the brown or yellow mice, the "you are what your mom ate" phenomenon reflects just such epigenetic influences. The Duke scientists fed female mice dietary supplements of vitamin B12, folic acid, betaine and choline just before and throughout their pregnancy. Offspring of mice eating a regular diet had yellowish fur; pups of the supplemented mothers, although genetically identical to the yellow mice, were brown.

When they grew up, the brown mice also had much lower rates of obesity, diabetes and cancer, Robert Waterland and Randy Jirtle of Duke's Department of Radiation Oncology report in the journal Molecular and Cellular Biology. Whatever the extra nutrients did to the fetal mice's genes didn't stop with fur color.

Actually, that "whatever" isn't quite fair. The Duke team knows exactly what the supplements did. All of the compounds contain a simple molecule called a methyl group, which is one carbon and three hydrogen atoms. For a little guy, methyl wields a big stick: It can turn genes off.

That's what happened in the brown mice. Methyl from the supplements switched off a gene called Agouti, which both gives a mouse a yellowish coat and makes it obese. The yellowish babies weren't suffering from any nutritional deficiency; it's just that their Agouti gene was still activated. "Nutritional supplementation to the mother can permanently alter gene expression in her offspring without mutating the genes themselves at all," says Prof. Jirtle.

That's the very essence of epigenetics.

The reason the Agouti gene was silenced is that it had the misfortune to lie next to an interloper. Mammalian genomes are riddled with bits of DNA that leap around like so many jumping beans. Called transposons, they sometimes wind up beside the on/off switch for an important gene, and are sitting ducks for those gene-silencing methyl groups. In the offspring of mouse moms eating methyl-rich dietary supplements, just such a jumping gene was silenced, with the result that the Agouti gene it had snuggled up to was also struck dumb.

This isn't just about yellow and brown mice. "About 40% of the human genome is transposons," notes Prof. Jirtle.

That means an awful lot of human genes could be targets of methylation, and so silenced. Whether that is good or bad depends on what the gene does. Silencing a gene that raises the risk of schizophrenia would be welcome. Silencing a tumor-suppressor gene wouldn't be. What's clear, he adds, is that "we, too, have genes -- including those influencing susceptibility to cancer, obesity and diabetes -- that can be turned off or on by epigenetic factors triggered by early nutrition and exposure to chemical agents."

Next week: How epigenetics might explain certain puzzles from cancer to birth defects.

Copyright 2003 Dow Jones & Company, Inc.

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New York Times

October 7, 2003

A Pregnant Mother's Diet May Turn the Genes Around

By Sandra Blakeslee

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.

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. Thomas 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. Peter 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. 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.

"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.

Copyright 2003 The New York Times Company

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Wall Street Journal July 16, 2004

By Sharon Begley

Mellow or Stressed?

Mom's Care Can Alter DNA of Her Offspring

If anyone out there still believes that DNA is destiny and that claims to the contrary are so much bleeding-heart, PC drivel (my favorite is that parents' treatment of their children has no effect on their character, beliefs, behavior or values), neuroscientist Michael Meaney has some rats he'd like you to meet.

Since the 1990s, he and his colleagues at McGill University, Montreal, have been documenting how mother rats affect their offspring (dads don't stick around to raise the kids). Now they have scored what neuroscientist Robert Sapolsky of Stanford University, Palo Alto, Calif., calls "a tour de force": proof that a mother's behavior causes lifelong changes in her offspring's DNA.

A decade ago Prof. Meaney noticed that newborn rats whose mothers rarely lick and groom them grow up... well, there is a fancy biochemical description for it, but let's just say that they grow up a bit of a neurotic mess. Pups of attentive moms grow up less fearful, more curious, mellower.

Prof. Meaney and his team then showed that this wasn't a case of mellow moms having mellow kids and neglectful moms having maladjusted kids, as the DNA-as-destiny crowd would have it. When the scientists switch around the newborns so that rat pups born to attentive moms are reared by standoffish moms, the pups grow up to be extremely stressed out, nearly jumping out of their skins at the slightest stress. Pups born to standoffish moms but reared by attentive ones grow up to be less fearful, more curious, more laid-back, taking stress in stride.

Rearing, it turns out, affects molecules in the brain that catch hold of stress hormones. Licking and grooming increases the number of these receptors. The more such receptors the brain has in the region called the hippocampus, the fewer stress hormones are released; the fewer the stress hormones coursing through its body, the mellower the rat.

It turns out that all newborn rats have a molecular silencer on their stress-receptor gene. In rats reared by standoffish mothers, the silencer remains attached, the scientists will report in the August issue of Nature Neuroscience. As a result, the brain has few stress-hormone receptors and reacts to stress like a skittish horse hearing a gunshot.

But licking and grooming by an attentive mother literally removes the silencer; the molecule is gone. Those baby rats have lots of stress-hormone receptors in their brains and less stress hormone, and they grow up to be curious, unafraid and able to handle stress.

"In the nature/nurture debate, people have long suspected that the environment somehow regulates the activity of genes," says Prof. Meaney. "The question has always been, how? It took four years, but we've now shown that maternal care alters the chemistry of the gene."

The discovery overturns genetic dogma so thoroughly -- after all, how mom treats the kids isn't supposed to alter something so fundamental as their DNA -- that one researcher reviewing Prof. Meaney's manuscript at a prominent American science journal said there is no precedent for such a claim, asserted that he simply didn't believe it, and recommended that the journal not publish it. The scientists at Nature disagreed.

A key unanswered question is whether DNA can change even later in life. That is, can rats who grow up to be skittish, because they were reared by standoffish mothers, mellow out as the result of some experience? And does parental care, or other experience, alter DNA in people, too?

It would be astonishing if it did not. Altering genes by adding or removing silencing molecules is part of a new field called epigenetics. If epigenetics were a film, it would be "Fahrenheit 9/11," the hot new release and one that is causing more than a bit of consternation among traditionalists. This year's Nobel Symposium in Stockholm featured epigenetics, as did the A-list annual conference of the Cold Spring Harbor Laboratory in New York. Last month, the National Institutes of Health announced a $5 million grant to Johns Hopkins University School of Medicine, Baltimore, to establish the Center for Epigenetics of Common Human Disease, the first of its kind.

Genetic changes are mutations in which one or more of the four chemicals that make up the twisting double helix of DNA is, typically, deleted or changed. Instead of ATTCTG, for instance, you have ATTGTG; as a result, the gene no longer functions as intended.

Epigenetic changes, in contrast, leave the sequence of As, Ts, Cs and Gs untouched. But the DNA acquires some new accessories, as it were: Certain small molecules glom onto the DNA, and suddenly a gene that was silent is active, or one that was active is hushed. That is what happened to Prof. Meaney's rats: A previously silenced gene began singing loud and clear.

The appeal of epigenetics is obvious to anyone who is or knows an identical twin. Despite having the exact same sequence of DNA, identical twins aren't identical, especially when it comes to diseases such as cancers and mental illness. Something has altered their DNA sequence so that disease-causing genes turn on or disease-suppressing genes turn off. I'll explore epigenetics further in next week's column.

Copyright 2004 Dow Jones & Company, Inc.

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Wall Street Journal July 23, 2004

By Sharon Begley

How a Second, Secret Genetic Code Turns Genes On and Off

July 23, 2004; Page A9

With some identical twins, a slightly different hairline or tilt of the eyebrows reveals who's who. But for this pair of brothers, the distinguishing trait is more obvious -- and more tragic: One has had schizophrenia since he was 22. His identical twin is healthy.

Like all identical twins, the brothers carry the exact same sequence of three billion chemical letters in their DNA (this is the sequence that the Human Genome Project famously decoded). So there was no sense in looking for a genetic difference among these usual suspects. But because schizophrenia is at least partly heritable, scientists suspected that the twins' DNA had to differ somewhere.

As I explained in last week's column1, there is a second, and largely secret, genetic code beyond the well-known one of As, Ts, Cs and Gs that make up the human genome sequence. Called "epigenetic," this second code acts like the volume control on a TV remote to silence or turn up the activity of genes. It was in these epigenetic changes that Arturas Petronis of the Centre for Addiction and Mental Health, Toronto, and his colleagues found the difference between the twins.

** Mellow or Stressed? Mom's Care Can Alter DNA of Her Offspring2 In the healthy brother, the scientists reported in 2003, molecular silencers sit on a gene that affects dopamine, a brain chemical. In the twin with schizophrenia, the molecular silencers were almost absent, so the gene was operating at full volume. In another pair of identical twins, both of whom have schizophrenia, the silencers were also missing.

A pattern had emerged: missing silencers are linked to schizophrenia, perhaps because that state of DNA triggers a profusion of dopamine receptors. Measured by this second genetic code, "the twin with schizophrenia was closer to these unrelated men than to his own twin brother," says Dr. Petronis.

This sort of DNA difference would never be detected with standard genetic tests, which scan for typos -- mutations -- in DNA sequences. But with the explosion in epigenetics, biologists are now realizing that changes that silence and unsilence genes, but leave the DNA sequence untouched, might explain complex diseases better than the sequence variations that have been the holy grail for 50 years.

Take cancer. Cells harbor tumor-suppressor genes that keep them from becoming malignant. But even when there is no mutation in tumor-suppressor genes, a cell can become cancerous. That left scientists scratching their heads. It turns out that tumor-suppressor genes can be abnormally silenced, by epigenetics, even when their DNA sequence (which genetic tests for cancer detect) is perfectly normal. So far, scientists have identified at least 60 presumably beneficial genes that are abnormally silenced in one or another cancer, allowing tumors to take hold.

Conversely, an unsilencing of cancer-causing genes allows these rogue genes to turn on, Andrew Feinberg of Johns Hopkins School of Medicine, Baltimore, and colleagues found. That triggers lung and colon cancers. "About 3% of genes seem to be abnormally silenced or activated in cancers," says Dr. Feinberg.

Last month, a Berlin-based biotech, Epigenomics AG, reported that the silence/unsilence pattern of one gene strongly predicts whether breast cancer is likely to recur. Fully 90% of the women in whom this gene was operating at normal volume were metastasis-free 10 years after treatment, compared with 65% in whom the gene was silenced. Presumably, the gene is involved in blocking metastasis, so silencing it spells trouble.

"Epigenetic changes are more clearly associated with the progression of tumors than mutations are," says Dr. Feinberg. "Epigenetics may be as important in certain conditions as the DNA sequence is in other cases."

One of the oddest discoveries in epigenetics is that genes inherited from mom and dad are not equal. Normally, the IGF2 gene you get from dad is active, but the copy from mom is silenced. In about 10% of people, however, the "be quiet" tag has been lost. The unsilenced IGF2 gene is associated with colorectal cancer, Dr. Feinberg and colleagues reported last year. Epigenomics AG is trying to turn the discovery into a simple blood test for colorectal cancer risk.

With age, silencers on genes seem to melt away, which might help explain why cancers and other diseases become more common the older you get. When one of the two parental genes for a protein called homocysteine is not properly silenced, the body produces a double dose of it; high levels are associated with heart disease and stroke.

It is too soon to infer dietary advice from all this, but some scientists suspect that diets too low in methyl, the molecule that usually silences genes, may spell trouble. Sources of methyl include folate (from liver, lentils and fortified cereals) and vitamin B-12 (in meat and fish).

Last fall, European scientists launched a "human epigenome project." It will scan DNA for "silence" tags and link them to disease. "The human epigenome needs to be mapped if we are ever going to thoroughly understand the causes of cancer and other complex diseases, which we can't explain by mutations in the DNA sequence," says Randy Jirtle of Duke University, Durham, N.C.

Let the race for this second genetic code begin.

Copyright 2004 Dow Jones & Company, Inc.

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New Scientist

April 12, 2005

Pregnant smokers increase grandkids' asthma risk

Women who smoke when pregnant may spark asthma in their grandchildren decades later, a new study discovers.

By Gaia Vince

A child whose maternal grandmother smoked while pregnant may have double the risk of developing childhood asthma compared with those with grandmothers who never smoked, say researchers from the University of Southern California, US. And the risk remains high even if the child's mother never smoked.

It has been known for some time that smoking while pregnant can increase the risk of the child developing asthma, but this is the first time that the toxic effects of cigarette smoke have been shown to damage the health of later generations. The researchers believe that the tobacco may be altering which genes are switched "on" or "off" in the fetus's reproductive cells, causing changes that are passed on to future generations.

Frank Gilliland, professor of preventative medicine at the Keck School of Medicine in Los Angeles, US, and colleagues interviewed the parents of 338 children who had asthma by the age of five and a control group of 570 asthma-free children. They found that children whose mothers smoked while pregnant were 1.5 times more likely to develop asthma that those born to non-smoking mothers.

But children whose grandmothers smoked when pregnant had, on average, 2.1 times the risk of developing asthma than children with grandmothers who never smoked. Even if the mother did not smoke, but the grandmother did, the child was still 1.8 times more likely to develop asthma. Those children whose mother and grandmother both smoked while pregnant had their risk elevated by 2.6 times.

Two-pronged effect Gilliland believes the trans-generational repercussions of smoking indicate that tobacco chemicals are having a two-pronged effect: by directly damaging the female fetus's immature egg cells -- putting future children at risk -- and also by damaging parts of the fetus's cells that are responsible for determining which genes will be expressed.

This second type of effect -- called an epigenetic effect -- could potentially alter which genes are expressed in the child's immune system which, in turn, Gilliland suspects, may increase the child's susceptibility to asthma.

"We did not study epigenetic changes directly, but this is one suggested mechanism that could account for our findings," he told New Scientist.

Stress hormones

But Marcus Pembrey, an epigenetics expert and director of genetics at the Avon Longitudinal Study of Parents and Children in Bristol, UK, says that the results Gilliland found were unlikely to have an epigenetic basis. "Since the effect has passed down the mother's line, the increase in asthma risk is more likely to be due to other factors. For example, the mother can pass stress hormones, metabolites or immune cells (lymphocytes) to the fetus while it is in utero, so these are more likely to affect the child's health later on."

"The epigenetic theory is a bit far-fetched in this case," he told New Scientist.

Gilliland admits that one of the limitations of his study was that the children may have acquired their asthma through passive smoking as a result of living in a smoky household where their mother, grandmother or other relatives smoked.

"Other studies suggest that in-utero exposure has an independent effect from second-hand smoke, but second-hand smoke may also play a role that we could not separate in this study," he comments, adding that further studies are needed.

Martyn Partridge, chief medical adviser to Asthma UK says: "The suggestion of an association with grand-maternal smoking is intriguing and whilst the authors' postulated explanations for this are very reasonable, confirmation of the association in other studies should be the next step."

Journal reference: Chest (vol 127, p 1232)

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Washington State University News Service

June 2, 2005

Surprising Study Shows Role of Toxins in Inherited Disease

PULLMAN, Wash. -- A disease you are suffering today could be a result of your great-grandmother being exposed to an environmental toxin during pregnancy.

Researchers at Washington State University [WSU] reached that remarkable conclusion after finding that environmental toxins can alter the activity of an animal's genes in a way that is transmitted through at least four generations after the exposure. Their discovery suggests that toxins may play a role in heritable diseases that were previously thought to be caused solely by genetic mutations. It also hints at a role for environmental impacts during evolution.

"It's a new way to think about disease," said Michael K. Skinner, director of the Center for Reproductive Biology. "We believe this phenomenon will be widespread and be a major factor in understanding how disease develops."

The work is reported in the June 3 issue of Science Magazine.

Skinner and a team of WSU researchers exposed pregnant rats to environmental toxins during the period that the sex of their offspring was being determined. The compounds -- vinclozolin, a fungicide commonly used in vineyards, and methoxychlor, a pesticide that replaced DDT -- are known as endocrine disruptors, synthetic chemicals that interfere with the normal functioning of reproductive hormones.

Skinner's group used higher levels of the toxins than are normally present in the environment, but their study raises concerns about the long-term impacts of such toxins on human and animal health. Further work will be needed to determine whether lower levels have similar effects.

Pregnant rats that were exposed to the endocrine disruptors produced male offspring with low sperm counts and low fertility. Those males were still able to produce offspring, however, and when they were mated with females that had not been exposed to the toxins, their male offspring had the same problems. The effect persisted through all generations tested, with more than 90 percent of the male offspring in each generation affected. While the impact on the first generation was not a surprise, the transgenerational impact was unexpected.

Scientists have long understood that genetic changes persist through generations, usually declining in frequency as the mutated form of a gene gets passed to some but not all of an animal's offspring. The current study shows the potential impact of so-called epigenetic changes.

Epigenetic inheritance refers to the transmission from parent to offspring of biological information that is not encoded in the DNA sequence. Instead, the information stems from small chemicals, such as methyl groups, that become attached to the DNA. In epigenetic transmission, the DNA sequences -- the genes -- remain the same, but the chemical modifications change the way the genes work. Epigenetic changes have been observed before, but they have not been seen to pass to later generations.

While this research focused on the impact of these changes on male reproduction, the results suggested that environmental influences could have multigenerational impacts on heritable diseases. According to Skinner, epigenetic changes might play a role in diseases such as breast cancer and prostate disease, whose frequency is increasing faster than would be expected if they were the result of genetic mutations alone.

The finding that an environmental toxin can permanently reprogram a heritable trait also may alter our concept of evolutionary biology. Traditional evolutionary theory maintains that the environment is primarily a backdrop on which selection takes place, and that differences between individuals arise from random mutations in the DNA. The work by Skinner and his group raises the possibility that environmental factors may play a much larger role in evolution than has been realized before. This research was supported in part by a grant to Skinner from the U.S. Environmental Protection Agency's STAR Program.

Related Web sites:

WSU Center for Reproductive Biology: {1}

Michael Skinner's Web site: {2}

Contact:

Michael Skinner, Center for Reproductive Biology, 509/335-1524, skinner@wsu.edu

{1} http://www.crb.wsu.edu/

{2} http://www.skinner.wsu.edu

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Forbes

June 2, 2005

Pesticides Cause Lasting Damage to Rats' Sperm

By Amanda Gardner

THURSDAY, June 2 (HealthDay News) -- Pregnant rats exposed to environmental toxins gave birth to four generations of males with decreased sperm function, a new study reports.

It's not clear what these findings mean for humans, but the researchers aren't discounting the potential significance.

"It's not a large leap to show that similar things could be happening in humans, but we need to show it," said Michael K. Skinner, senior author of the study and a professor of molecular biosciences and director of the Center for Reproductive Biology at Washington State University, in Pullman, Wash.

Perhaps more important, the findings also show that one exposure to an environmental toxin can generate permanent effects evident in several subsequent generations of rats -- and possibly other species, including humans, Skinner said.

"If a pregnant woman is exposed to that environmental toxin during mid-gestation, it could actually cause a disease state in adult offspring which is heritable," he explained. "It looks like male sperm is being affected and permanently reprogrammed."

The study appears in the June 3 issue of the journal Science.

Dr. Frederick Licciardi, associate director of reproductive endocrinology at New York University Medical Center, said there was no reason for humans to be unduly alarmed, but the various implications of the new findings were significant.

"Just the fact that there might be ways to epigenetically change the fetus from generation to generation by something that happens with the female rat or human is also interesting," he said.

Added Shanna Swan, a professor in the department of obstetrics and gynecology at the University of Rochester School of Medicine and Dentistry: "As a reproductive and environmental epidemiologist, this seems extremely important, because it may provide a mechanism to account for rapid changes in reproductive parameters over time (such as decreases in sperm concentration) which have been so puzzling."

Various environmental toxins, as well as radiation and chemotherapy, can cause genetic and development defects in offspring if a mother is exposed while pregnant. These changes are usually changes in DNA sequence and affect only one generation, the study researchers said.

To have an effect over more than one generation of offspring, the change needs to be an "epigenetic" one, meaning there is a chemical modification of the DNA.

For this study, the researchers exposed pregnant female rats to vinclozolin, a fungicide used heavily in the wine industry, and methoxychlor, a pesticide which is used as a DDT replacement. Both are endocrine -- or hormone -- disruptors.

The exposure took place at the time when gender was being determined and the testes and ovaries being developed.

Sperm numbers were reduced 20 percent and sperm motility about 25 percent to 35 percent for the rats exposed to vinclozolin. Similar effects were seen with methoxychlor. Ninety percent of all males in the next four generations experienced permanent changes in their DNA, Skinner said.

"That kind of a frequency cannot be attributed to a genetic mutation involving DNA sequence so it's epigenetic," Skinner explained. "We've changed that imprint."

The rats were exposed to higher doses of the toxins than humans would normally get in the environment. "We can't claim anything about the toxicology of the compounds for the human population," Skinner said. "We now need to go back and do the dose curves."

"The dose used was 200 milligrams per kilogram, which is just an unrealistic exposure as far as humans would expect," Licciardi added.

But there are implications beyond the impact of a specific toxin on a specific animal.

"We now need to think about how diseases develop. Epigenetics could be a major factor we didn't previously appreciate," Skinner said. "We need to evaluate environmental factors as a factor in evolutionary biology. It may explain why certain subpopulations evolve differently. This issue has a broader impact than just fertility."

Copyright 2005 Forbes.com Inc.

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Time Magazine Online Edition

June 3, 2005

Could Toxin Damage Become Hereditary?

By Michael Lemonick

Pregnant women are advised to avoid environmental toxins to prevent harm to their babies. But a new study out of Washington State University suggests that by heeding those warnings they could also be sparing their great-grandchildren from fertility problems.

The study, published in Thursday's issue of Science, involved exposing rats to two common agricultural chemicals -- the fungicide vinclozolin and the pesticide methoxychlor. Both are chemically related to natural hormones, and have been tentatively implicated in reproductive disorders in both animals and humans. When the rats gave birth, their male offspring tended to have low sperm counts and low fertility. None of that was a surprise. But what did surprise researchers was the fact that when these males did manage to reproduce, their offspring also had low sperm counts. And so did the generation after that -- more than 90% of the males in each generation were affected.

If the same effect occurs in humans -- a reasonable hypothesis -- it could imply that keeping poisons out of the environment becomes even more important than previously realized. Michael K. Skinner, director of the University's Center for Reproductive Biology, suggests that that the new findings on toxin damage being transmitted across generations could even help explain the dramatic rise in breast and prostate cancer in recent decades as partly due to the cumulative effect of various toxins over several generations.

Copyright 2005 Time Inc.

http://time.blogs.com/daily_rx/2005/06/you_are_what_yo.html

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Seattle Post-Intelligencer

June 3, 2005

Startling study on toxins' harm

WSU findings show that disorders can be passed on without genetic mutations

By Tom Paulson

It's just a study involving a few rats with fertility problems in Pullman [Washington], but the findings could lead to fundamental changes in how we look at environmental toxins, cancer, heritable diseases, genetics and the basics of evolutionary biology.

If a pregnant woman is exposed to a pesticide at the wrong time, the study suggests, her children, grandchildren and the rest of her descendants could inherit the damage and diseases caused by the toxin -- even if it doesn't involve a genetic mutation.

"As so often happens in science, we just stumbled onto this," said Dr. Michael Skinner, director of the center for reproductive biology at Washington State University.

Skinner's team at WSU and colleagues from several other universities report in today's Science magazine on what they believe is the first demonstration and explanation of how a toxin-induced disorder in a pregnant female can be passed on to children and succeeding generations without changes in her genetic code, or DNA.

"We were quite surprised... we've been sitting on this for a few years," said Skinner, who is expected to present his findings today at a scientific meeting in San Diego.

The report in Science, entitled "Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility," also sounds like an attempt to avoid attention. That's unlikely to work. The findings prompt serious and, in some cases, disturbing questions about a number of basic assumptions in biology.

The standard view of heritable disease is that for any disorder or disease to be inherited, a gene must go bad (mutate) and that gene must get passed on to the offspring.

What Skinner and his colleagues did is show that exposing a pregnant rat to high doses of a class of pesticides known as "endocrine disruptors" causes an inherited reproductive disorder in male rats that is passed on without any genetic mutation.

It's not genetic change; it's an "epigenetic" change. Epigenetics is a relatively new field of science that refers to modifying DNA without mutations in the genes.

"It's not a change in the DNA sequence," Skinner explained. "It's a chemical modification of the DNA."

Scientists have known for years about these changes to DNA that can modify genes' behavior without directly altering them.

One form of epigenetic change is natural. Every cell in the body contains the entire genetic code. But brain cells must use only the genes needed in the brain, for example, and kidney cells should activate only the genes needed for renal function.

Cells commonly switch on and off gene behavior by attaching small molecules known as methyl groups to specific sections of DNA. The attachment and detachment of methyl groups is also an important process in fetal development of the male testes and female ovaries -- which is where Skinner got started on this.

But the common wisdom has been that any artificially induced epigenetic modifications will remain as an isolated change in an individual. Because no genes get altered, the changes cannot be passed on.

"We showed that they can be," Skinner said.

The experiment got its start four years ago by accident. His lab was studying testes development in fetal rats, using a fungicide used in vineyards (vinclozin) and a common pesticide (methoxychlor) to disrupt the process. A researcher inadvertently allowed two of the exposed rats to breed, so the scientists figured they'd just see what happened.

The male in the breeding pair was born with a low sperm count and other disorders because of the mother's exposure to toxins. No surprise. But the male offspring of the pair also had these problems, as did the next two generations of male rats.

"I couldn't explain it," Skinner. This wasn't supposed to happen.

The scientists didn't tell anyone about their finding and continued, for the next two years, to confirm that it was real and to find an explanation. Eventually, they documented that a toxin-induced attachment of methyl groups to DNA in the mother rat was being passed on to offspring.

"In human terms, this would mean if your great grandmother was exposed to an environmental toxin at a critical point in her pregnancy, you may have inherited the disease," Skinner said.

While the study was focused on a heritable disorder of reproduction in rats, he said there's every reason to believe this can happen for other diseases -- such as cancer.

"There has been this speculation that the increased rates of some cancers may be due to environmental factors, but they've never been able to describe a mechanism to explain this," Skinner said.

The findings also suggest a reconsideration of one of the basic tenets of evolutionary biology -- that evolution proceeds by random genetic change.

The standard view is that the environment has no direct influence, except in how it may favor or discriminate against the creatures with the latest genetic mutations.

The WSU study, Skinner said, suggests the possibility that environmental factors such as toxins may also directly cause heritable changes in creatures. "Epigenetics may be just as important as genetics in evolution," he said.

P-I reporter Tom Paulson can be reached at 206-448-8318 or tompaulson@seattlepi.com

Copyright 1998-2005 Seattle Post-Intelligencer

 


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