Jun 092005
 

—–Original Message—– From: Sandra Finley  Sent: June 14, 2005

Many thanks to Cathy who writes “Thought you’d find this interesting, and rather alarming too.” I hate to think that we specialize in “the alarming” – but, well, … in my next life I’m coming back as an ostrich!”

– – – – – – – – – – – – – – – – – – – – – – – – – – – – –

SEE ALSO:   (2012-05-23)   Interview with Dr. David Crews, Epigenetic Transgenerational Inheritance, Chemical damage can be inherited by offspring through unlimited generations

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Appended are related articles, courtesy of Rachel’s archives:

 

Time Magazine Online Edition June 3, 2005

Seattle Post-Intelligencer June 3, 2005

Washington State University News Service June 2, 2005

Forbes June 2, 2005

Wall Street Journal July 23, 2004

Wall Street Journal July 16, 2004

New Scientist April 12, 2005

Wall Street Journal August 15, 2003

New York Times October 7, 2003

 

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RACHEL’S ENVIRONMENT & HEALTH NEWS #819

http://www.rachel.org

June 9, 2005

 

A NEW WAY TO INHERIT ENVIRONMENTAL HARM

 

by Tim Montague*

 

New research shows that the environment is more important to

health than anyone had imagined. Recent information indicates

that toxic effects on health can be inherited by children and

grandchildren, even when there are no genetic mutations

involved.[1] These inherited changes are caused by subtle

chemical influences, and this new field of scientific inquiry

is called “epigenetics.”[2]

 

Since the 1940s, scientists have known that genes carry

information from one generation to the next, and that genes

gone haywire can cause cancer, diabetes, and other diseases.

But scientists have also known that genes aren’t the whole

story because identical twins — whose genes are identical —

can have very different medical histories. One identical twin

can be perfectly healthy while the other develops schizophrenia

or cancer — so the environment must play a significant role,

not merely genes.

 

What’s surprising is that scientists are now revealing that

these environmental effects can be passed from one generation

to the next by a process called “epigenetics,” with

far-reaching implications for human health. Epigenetics is

showing that environmental influences can be inherited — even

without any mutations in the genes themselves[1] — and may

continue to influence the onset of diseases like diabetes,

obesity, mental illness and heart disease, from generation to

 

In other words, the cancer you get today may have been caused

by your grandmother’s exposure to an industrial poison 50 years

ago, even though your grandmother’s genes were not changed by

the exposure.[1] Or the mercury you’re eating today in fish may

not harm you directly, but may harm your grandchildren.

 

This emerging field of epigenetics is causing a revolution in

the understanding of environmental influences on health. The

field is only about 20 years old, but is becoming

well-established. In 2004, the National Institutes of Health

granted $5 million to the Johns Hopkins Medical School in

Baltimore to start the Center for Epigenetics of Common Human

 

The latest information appears in a new study by Michael

Skinner and colleagues at the University of Washington,

published in the June 3 issue of Science magazine. Skinner

found that mother rats exposed to hormone-mimicking chemicals

during pregnancy gave birth to four successive generations of

male offspring with significantly reduced fertility.[3] Only

the first generation of mothers was exposed to a toxin, yet

four generations later the toxic effect could still be

 

Prior to this study, scientists had only been able to document

epigenetic effects on the first generation of offspring. These

new findings suggest that harm from toxins in the environment

can be much longer lasting and pervasive than previously known

because they can impact several generations.

 

And therefore a precautionary approach to toxics is even more

important that previously believed. (See Rachel’s 765, 770, 775,

781, 787, 789, 790, 791, 802, 803, 804.)

 

Over the past sixty years doctors and scientists have pieced

together a picture of the genetic basis for life and some of

the genetic causes of! human and animal disease. Genes regulate

the production of proteins — the essential building blocks of

life. Genes are composed of a finite series of letters (a code

made up of Cs, Ts, As, and Gs, each representing a nucleotide)

embedded in long strands of DNA. DNA is the large molecule,

composed of genes, that carries the genetic inheritance forward

into the next generation.

 

There are approximately three billion ‘letters’ in the human

genetic code. Science has long understood that when a gene

mutates — that is, when a typo is introduced — it can have

far-reaching effects for the cell, the tissue and the organism

as a whole. For example, a genetic mutation caused by too much

sun (ultraviolet radiation), could result in abnormal

uncontrolled cell growth which could lead to skin cancer which

could spread throughout your body. Stay in the shade and you

reduce your risk.

 

But now scientists are seeing that disease can be passed from

generation to generation without any genetic mutations.[1] The

DNA molecule itself gets another molecule attached to it, which

changes the behavior of the genes without changing the genes

themselves.[1] The attachment of these additional molecules is

caused by environmental influences — but these influences can

then be passed from one generation to the next, if they affect

the germ cells, i.e., the sperm or the egg.

 

Scientists have, so far, discovered three different kinds of

“epigenetic” changes that can affect the DNA molecule and thus

cause inheritable changes. One is the methyl molecule.

 

Scientists began to see direct connections between human

diseases like cancer and these subtle genetic variations like

methylation in 1983 when Andrew Feinberg and his colleagues at

Johns Hopkins found that cancer cells had unusually low

incidence of DNA-methylation.[4]

 

Methyl is a molecule of one carbon atom and three hydrogen

atoms. Together they attach to a strand of DNA altering its

three-dimensional structure and the behavior of specific genes

in the DNA strand. It turns out that methylation works like a

volume control for the activity of individual genes. Whereas

genetic mutations are typos and relatively easy to test for,

epigenetic changes are analogous to the formatting of the text

(e.g. font, size, and color) and are much less-well understood.

Over the past 20 years, Feinberg and many other cancer

specialists have documented the wide-spread influence of

epigenetics on the development of cancer in humans and

laboratory animals.[5]

 

So epigenetics is changing our traditional picture of common

chemicals, like DDT. DDT is a powerful environmental toxin —

once it enters a living thing it mimics the behavior of natural

hormones — resulting in abnormal sexual and reproductive

development. Widespread use of DDT in the 1940s and 1950s is

associated with large scale declines in some bird populations

(like the Peregrin falcon) because DDT causes birds’ eggshells

to thin, and thus the eggs crack before the embryo can develop

into a chick.

 

When persistent environmental pollutants (like DDT) are phased

out, we might be falsely lulled into believing that we have

solved the problem. The thinking is logical — remove the toxin

from the environment and you get rid of the toxic effects. Not

so according to the findings of Skinner and his colleagues.

 

The Skinner study tells us that phasing out dangerous toxins

doesn’t end the problem — because the damage done by exposures

decades ago could still flow from generation to generation via

epigenetic pathways.

 

Skinner and his colleagues treated groups of pregnant rats,

some with methoxychlor and some with vinclozolin. Methoxychlor

is a replacement for DDT, a pesticide used on crops and

livestock and in anima! l feed. Vinclozolin is a fungicide widely

used in the wine industry. It is just one of a suite of widely

used chemicals from flame-retardants to ingredients in plastics

that can cause reproductive abnormalities in laboratory

 

Both methoxychlor and vinclozolin are known hormone disruptors

(see Rachel’s 486, 487, 499, 501, and 547). Male offspring of

these pesticide-treated mothers had reduced fertility (lower

sperm count, reduced sperm quality), which was not a surprising

finding. The scientists then bred these offspring, and again

the male offspring had reduced fertility. This came as a complete

surprise. Over 90% of the male offspring in four generations of

the test animals had reduced fertility.

 

Skinner’s report concludes that genetic mutations are highly

unlikely to produce such a strong signal in the treated animals

and that DNA-methylation is the likely mechanism responsible

for the observed decline in male fertility.

 

Treating the mother rats during pregnancy apparently

re-programmed the genetic material in the male offspring so

that all subsequent male offspring suffered lower fertility

from this environmental factor.

 

Skinner believes that his findings in rats could explain the

dramatic rise in breast and prostate cancers in humans in

recent decades (see Rachel’s 346, 369, 375, 385 and 547) as

partly due to the cumulative effects of multiple toxins over

several generations.

 

Skinner acknowledges that the doses he gave his rats were high,

compared to the doses humans might expect to receive from

environmental exposures. He is continuing his rat experiments

with lower doses now.

 

Of course all this new information makes the control of toxic

chemicals even more important that previously thought. The

health of future generations is at stake.

 

The development of epigenetics also greatly complicates

toxicity tes! ting, and chemical risk assessment. Epigenetics

tells us that much additional toxicity testing will

be needed. So far, there are no standardized,

government-approved protocols for conducting epigenetic tests.

Until such protocols emerge (which could take years), and a

great deal of expensive testing has been completed (requiring

many more years), risk assessors will have to acknowledge that

— so far as epigenetics is concerned — they are flying blind.

 

=====

 

* Tim Montague is Associate Director of Environmental Research

Foundation. He holds an M.S. degree in ecology from

University of Wisconsin-Madison and lives in Chicago.

 

[1] Here we define a genetic mutation as a change in the

sequence of nucleotide bases (C,A,T,G). We recognize that

epigenetic changes are heritable changes to the DNA, but they

are not sequence changes.

 

[2] To see nine articles on epigenetics from the popular press,

including an excellent series from the Wall Street Journal, go

to http://www.rachel.org/library/getfile.cfm?ID=531

 

[3] M. Anway, A. Cupp, M. Uzumcu, and M. Skinner, “Epigenetic

Transgenerational Actions of Endocrine Disruptors and Male

Fertility,” SCIENCE Vol. 308 (June 3, 2005), pgs. 1466-1469.

Michael Skinner is director of the University of Washington’s

Center for Reproductive Biology; http://www.skinner.wsu.edu

 

[4] Andrew Feinberg and Bert Vogelstein, “Hypomethylation

distinguishes genes of some human cancers from their normal

counterparts,” NATURE Vol. 301 (January 6, 1983), pgs. 89-92.

 

[5] Andrew Feinberg and Benjamin Tycko, “The history of cancer

epigenetics,” NATURE REVIEWS (February 2004) Vol. 4, pgs.

143-153.

 

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RACHEL’S ENVIRONMENT & HEALTH NEWS

Environmental Research Foundation

P.O. Box 160

New Brunswick, N.J. 08903

Fax (732) 791-4603; E-mail: erf@rachel.org

 

SUBSCRIPTIONS

 

Subscriptions are free. To subscribe, send E-mail

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in the message.

 

SPANISH EDITION

 

The Rachel newsletter is also available in Spanish; to learn

how to subscribe in Spanish, send the word AYUDA in an E-mail

message to info@rachel.org.

 

BACK ISSUES IN ENGLISH AND SPANISH

 

All back issues are on the web at: http://www.rachel.org in

text and PDF formats.

 

COPYRIGHT NOTICE

 

Permission to reprint Rachel’s is hereby granted to everyone,

though we ask that you not change the contents and we ask that

you provide proper attribution.

 

In accordance with Title 17 U.S.C. Section 107 this material is

distributed without profit to those who have expressed a prior

interest in receiving it for research and educational purposes.

 

Some of this material may be copyrighted by others. We believe

we are making “fair use” of the material under Title 17, but if

you choose to use it for your own purposes, you will need to

consider “fair use” in your own case. –Peter Montague, editor

 

============================================

http://www.rachel.org/library/getfile.cfm?ID=531

 

Nine rrticles about epigenetics from the popular press, in chronological

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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

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

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

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

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

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

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

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.

========================================================

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.

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.

===============================================================

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

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

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

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)

===========================================================

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

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

=========================================================

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,

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

“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 —

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.

=========================================================

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

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

===========================================================

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

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

Many thanks to Cathy who writes “Thought you’d find this interesting, and

rather alarming too.” I hate to think that we specialize in “the

alarming” – but, well, … in my next life I’m coming back as an ostrich!

/Sandra

================================

 

Appended are related articles, courtesy of Rachel’s archives:

 

Time Magazine Online Edition June 3, 2005

Seattle Post-Intelligencer June 3, 2005

Washington State University News Service June 2, 2005

Forbes June 2, 2005

Wall Street Journal July 23, 2004

Wall Street Journal July 16, 2004

New Scientist April 12, 2005

Wall Street Journal August 15, 2003

New York Times October 7, 2003

 

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

RACHEL’S ENVIRONMENT & HEALTH NEWS #819

http://www.rachel.org

June 9, 2005

 

A NEW WAY TO INHERIT ENVIRONMENTAL HARM

 

by Tim Montague*

 

New research shows that the environment is more important to

health than anyone had imagined. Recent information indicates

that toxic effects on health can be inherited by children and

grandchildren, even when there are no genetic mutations

involved.[1] These inherited changes are caused by subtle

chemical influences, and this new field of scientific inquiry

is called “epigenetics.”[2]

 

Since the 1940s, scientists have known that genes carry

information from one generation to the next, and that genes

gone haywire can cause cancer, diabetes, and other diseases.

But scientists have also known that genes aren’t the whole

story because identical twins — whose genes are identical —

can have very different medical histories. One identical twin

can be perfectly healthy while the other develops schizophrenia

or cancer — so the environment must play a significant role,

not merely genes.

 

What’s surprising is that scientists are now revealing that

these environmental effects can be passed from one generation

to the next by a process called “epigenetics,” with

far-reaching implications for human health. Epigenetics is

showing that environmental influences can be inherited — even

without any mutations in the genes themselves[1] — and may

continue to influence the onset of diseases like diabetes,

obesity, mental illness and heart disease, from generation to

 

In other words, the cancer you get today may have been caused

by your grandmother’s exposure to an industrial poison 50 years

ago, even though your grandmother’s genes were not changed by

the exposure.[1] Or the mercury you’re eating today in fish may

not harm you directly, but may harm your grandchildren.

 

This emerging field of epigenetics is causing a revolution in

the understanding of environmental influences on health. The

field is only about 20 years old, but is becoming

well-established. In 2004, the National Institutes of Health

granted $5 million to the Johns Hopkins Medical School in

Baltimore to start the Center for Epigenetics of Common Human

 

The latest information appears in a new study by Michael

Skinner and colleagues at the University of Washington,

published in the June 3 issue of Science magazine. Skinner

found that mother rats exposed to hormone-mimicking chemicals

during pregnancy gave birth to four successive generations of

male offspring with significantly reduced fertility.[3] Only

the first generation of mothers was exposed to a toxin, yet

four generations later the toxic effect could still be

 

Prior to this study, scientists had only been able to document

epigenetic effects on the first generation of offspring. These

new findings suggest that harm from toxins in the environment

can be much longer lasting and pervasive than previously known

because they can impact several generations.

 

And therefore a precautionary approach to toxics is even more

important that previously believed. (See Rachel’s 765, 770, 775,

781, 787, 789, 790, 791, 802, 803, 804.)

 

Over the past sixty years doctors and scientists have pieced

together a picture of the genetic basis for life and some of

the genetic causes of! human and animal disease. Genes regulate

the production of proteins — the essential building blocks of

life. Genes are composed of a finite series of letters (a code

made up of Cs, Ts, As, and Gs, each representing a nucleotide)

embedded in long strands of DNA. DNA is the large molecule,

composed of genes, that carries the genetic inheritance forward

into the next generation.

 

There are approximately three billion ‘letters’ in the human

genetic code. Science has long understood that when a gene

mutates — that is, when a typo is introduced — it can have

far-reaching effects for the cell, the tissue and the organism

as a whole. For example, a genetic mutation caused by too much

sun (ultraviolet radiation), could result in abnormal

uncontrolled cell growth which could lead to skin cancer which

could spread throughout your body. Stay in the shade and you

reduce your risk.

 

But now scientists are seeing that disease can be passed from

generation to generation without any genetic mutations.[1] The

DNA molecule itself gets another molecule attached to it, which

changes the behavior of the genes without changing the genes

themselves.[1] The attachment of these additional molecules is

caused by environmental influences — but these influences can

then be passed from one generation to the next, if they affect

the germ cells, i.e., the sperm or the egg.

 

Scientists have, so far, discovered three different kinds of

“epigenetic” changes that can affect the DNA molecule and thus

cause inheritable changes. One is the methyl molecule.

 

Scientists began to see direct connections between human

diseases like cancer and these subtle genetic variations like

methylation in 1983 when Andrew Feinberg and his colleagues at

Johns Hopkins found that cancer cells had unusually low

incidence of DNA-methylation.[4]

 

Methyl is a molecule of one carbon atom and three hydrogen

atoms. Together they attach to a strand of DNA altering its

three-dimensional structure and the behavior of specific genes

in the DNA strand. It turns out that methylation works like a

volume control for the activity of individual genes. Whereas

genetic mutations are typos and relatively easy to test for,

epigenetic changes are analogous to the formatting of the text

(e.g. font, size, and color) and are much less-well understood.

Over the past 20 years, Feinberg and many other cancer

specialists have documented the wide-spread influence of

epigenetics on the development of cancer in humans and

laboratory animals.[5]

 

So epigenetics is changing our traditional picture of common

chemicals, like DDT. DDT is a powerful environmental toxin —

once it enters a living thing it mimics the behavior of natural

hormones — resulting in abnormal sexual and reproductive

development. Widespread use of DDT in the 1940s and 1950s is

associated with large scale declines in some bird populations

(like the Peregrin falcon) because DDT causes birds’ eggshells

to thin, and thus the eggs crack before the embryo can develop

into a chick.

 

When persistent environmental pollutants (like DDT) are phased

out, we might be falsely lulled into believing that we have

solved the problem. The thinking is logical — remove the toxin

from the environment and you get rid of the toxic effects. Not

so according to the findings of Skinner and his colleagues.

 

The Skinner study tells us that phasing out dangerous toxins

doesn’t end the problem — because the damage done by exposures

decades ago could still flow from generation to generation via

epigenetic pathways.

 

Skinner and his colleagues treated groups of pregnant rats,

some with methoxychlor and some with vinclozolin. Methoxychlor

is a replacement for DDT, a pesticide used on crops and

livestock and in anima! l feed. Vinclozolin is a fungicide widely

used in the wine industry. It is just one of a suite of widely

used chemicals from flame-retardants to ingredients in plastics

that can cause reproductive abnormalities in laboratory

 

Both methoxychlor and vinclozolin are known hormone disruptors

(see Rachel’s 486, 487, 499, 501, and 547). Male offspring of

these pesticide-treated mothers had reduced fertility (lower

sperm count, reduced sperm quality), which was not a surprising

finding. The scientists then bred these offspring, and again

the male offspring had reduced fertility. This came as a complete

surprise. Over 90% of the male offspring in four generations of

the test animals had reduced fertility.

 

Skinner’s report concludes that genetic mutations are highly

unlikely to produce such a strong signal in the treated animals

and that DNA-methylation is the likely mechanism responsible

for the observed decline in male fertility.

 

Treating the mother rats during pregnancy apparently

re-programmed the genetic material in the male offspring so

that all subsequent male offspring suffered lower fertility

from this environmental factor.

 

Skinner believes that his findings in rats could explain the

dramatic rise in breast and prostate cancers in humans in

recent decades (see Rachel’s 346, 369, 375, 385 and 547) as

partly due to the cumulative effects of multiple toxins over

several generations.

 

Skinner acknowledges that the doses he gave his rats were high,

compared to the doses humans might expect to receive from

environmental exposures. He is continuing his rat experiments

with lower doses now.

 

Of course all this new information makes the control of toxic

chemicals even more important that previously thought. The

health of future generations is at stake.

 

The development of epigenetics also greatly complicates

toxicity tes! ting, and chemical risk assessment. Epigenetics

tells us that much additional toxicity testing will

be needed. So far, there are no standardized,

government-approved protocols for conducting epigenetic tests.

Until such protocols emerge (which could take years), and a

great deal of expensive testing has been completed (requiring

many more years), risk assessors will have to acknowledge that

— so far as epigenetics is concerned — they are flying blind.

 

=====

 

* Tim Montague is Associate Director of Environmental Research

Foundation. He holds an M.S. degree in ecology from

University of Wisconsin-Madison and lives in Chicago.

 

[1] Here we define a genetic mutation as a change in the

sequence of nucleotide bases (C,A,T,G). We recognize that

epigenetic changes are heritable changes to the DNA, but they

are not sequence changes.

 

[2] To see nine articles on epigenetics from the popular press,

including an excellent series from the Wall Street Journal, go

to http://www.rachel.org/library/getfile.cfm?ID=531

 

[3] M. Anway, A. Cupp, M. Uzumcu, and M. Skinner, “Epigenetic

Transgenerational Actions of Endocrine Disruptors and Male

Fertility,” SCIENCE Vol. 308 (June 3, 2005), pgs. 1466-1469.

Michael Skinner is director of the University of Washington’s

Center for Reproductive Biology; http://www.skinner.wsu.edu

 

[4] Andrew Feinberg and Bert Vogelstein, “Hypomethylation

distinguishes genes of some human cancers from their normal

counterparts,” NATURE Vol. 301 (January 6, 1983), pgs. 89-92.

 

[5] Andrew Feinberg and Benjamin Tycko, “The history of cancer

epigenetics,” NATURE REVIEWS (February 2004) Vol. 4, pgs.

143-153.

 

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

RACHEL’S ENVIRONMENT & HEALTH NEWS

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P.O. Box 160

New Brunswick, N.J. 08903

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BACK ISSUES IN ENGLISH AND SPANISH

 

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COPYRIGHT NOTICE

 

Permission to reprint Rachel’s is hereby granted to everyone,

though we ask that you not change the contents and we ask that

you provide proper attribution.

 

In accordance with Title 17 U.S.C. Section 107 this material is

distributed without profit to those who have expressed a prior

interest in receiving it for research and educational purposes.

 

Some of this material may be copyrighted by others. We believe

we are making “fair use” of the material under Title 17, but if

you choose to use it for your own purposes, you will need to

consider “fair use” in your own case. –Peter Montague, editor

 

============================================

http://www.rachel.org/library/getfile.cfm?ID=531

 

Nine rrticles about epigenetics from the popular press, in chronological

===========================================================

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.

============================================================

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

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

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

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

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

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

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

===========================================================

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

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.

========================================================

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.

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.

===============================================================

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

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

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

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)

===========================================================

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

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

=========================================================

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,

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

“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 —

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.

=========================================================

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

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

===========================================================

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

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

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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