—–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
================================
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 than previously thought. The
health of future generations is at stake.
The development of epigenetics also greatly complicates
toxicity testing, 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
Environmental Research Foundation
P.O. Box 160
New Brunswick, N.J. 08903
Fax (732) 791-4603; E-mail: erf@rachel.org
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message to info@rachel.org.
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
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.
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In accordance with Title 17 U.S.C. Section 107 this material is
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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
