[Pharmwaste] Epigenetics - Chemicals can turn genes on and off; new tests needed, scientists say.

[DeBiasi,Deborah]

http://www.environmentalhealthnews.org/ehs/news/epigenetics-workshop


Chemicals can turn genes on and off; new tests needed, scientists say. 

A National Academies workshop examined the evidence of epigenetic
effects and considered whether the thousands of chemicals in use today
should be tested for them. Some pollutants and chemicals don't kill
cells or mutate DNA. Instead, they may be more subtle, muting genes or
turning them on at the wrong time, which can lead to diseases that are
passed on for generations. Asthma in New York City children exposed to
traffic exhaust is an example, experts say. 

By Bette Hileman
Environmental Health News
Aug. 3, 2009

Each of us starts life with a particular set of genes, 20,000 to 25,000
of them. Now scientists are amassing a growing body of evidence that
pollutants and chemicals might be altering those genes-not by mutating
them, but by sending subtle signals that silence them or switch them on
at the wrong times.

Last week, several dozen researchers and experts convened by the
National Academies tackled this complicated topic, called epigenetics,
at a two-day workshop in Washington, D.C. They discussed new findings
that suggest chemicals in our environment and in our food can alter
genes, leaving people vulnerable  to a variety of diseases and
disorders, including diabetes, asthma, cancer and obesity. They also
considered whether regulatory agencies and industry should start testing
the thousands of chemicals in use today for these effects.

"There is little doubt these epigenetic effects are important. The next
question is how we test for effects," said William H. Farland, professor
of environmental and radiological health sciences at Colorado State
University. "We don't need to abandon current approaches to chemical
testing. When testing chemicals in animals, we may just need to add some
new endpoints."

 
  
Linda S. Birnbaum, Director of the National Institute of Environmental
Health Sciences 

Exposure to gene-altering substances, particularly in the womb and
shortly after birth, "can lead to increased susceptibility to disease,"
said Linda S. Birnbaum, who was named director of the National Institute
of Environmental Health Sciences and of the National Toxicology Program
in December. "The susceptibility persists long after the exposure is
gone, even decades later. Glands, organs, and systems can be permanently
altered."

 Animal studies indicate that some environmental chemicals cause
epigenetic changes that trigger breast and prostate cancer, obesity,
diabetes, heart disease, asthma, Alzheimer's, Parkinson's disease and
learning disabilities, she said.  And some new human studies are now
adding to the evidence.

"There is a huge potential impact from these exposures, partly because
the changes may be inherited across generations. You may be affected by
what your mother and grandmother were exposed to during pregnancy,"
Birnbaum said. "There is a huge potential impact from these exposures,
partly because the changes may be inherited across generations. You may
be affected by what your mother and grandmother were exposed to during
pregnancy." Linda Birnbaum, Director, National Institute of
Environmental Health Sciences
What a pregnant mother eats and the chemicals she is exposed to can
affect her offspring without causing mutations in the DNA, the experts
said. Instead, such exposures can disrupt the way that genes behave,
according to both animal and human studies. These changes, in turn, can
be passed on to the next generations.

Some environmental chemicals enable methyl groups (carbon atoms with
three hydrogen atoms attached) to attack genes, which turns them off or
mutes them, at a time when they should be turned on. When genes are
turned off, they can't direct the manufacture of proteins that are
essential for proper cell function. Chemicals also can uncoil parts of
the chromosome, causing genes to be expressed, or turned on, at
inappropriate times.

An example is asthmatic children. Wan-Yee Tang, a researcher at the
University of Cincinnati, found that children in New York City exposed
in the womb to high levels of polycyclic aromatic hydrocarbons (PAHs),
common air pollutants from traffic, were much more likely to have asthma
than those who were not exposed. By studying cord blood, she found that
a particular gene (ACSL3) was methylated in the asthmatic children and
unmethylated in the unexposed children, and concluded that the abnormal
methylation patterns probably caused the asthma.

The finding could in part explain why worldwide asthma rates have
skyrocketed in much of the world, reaching epidemic proportions among
children. In the boroughs of New York City with the worst air pollution,
about 25 percent of children are asthmatic.

Epigenetic changes also have been observed in children conceived with
assisted reproductive technologies, said Richard Meehan of the Medical
Research Council in Scotland.

One of the disorders that occurs at a higher rate in these children is
Beckwith-Wiedemann syndrome, which is characterized by abdominal wall
defects and a higher risk of certain childhood cancers. The culture
medium where fertilized eggs are grown for several days before
implantation probably causes the syndrome, he said. It appears that all
the different media used for the eggs might be problematic because they
contain chemicals that stimulate the addition of methyl groups to the
cells.

The scientists at the workshop said it's important to understand
epigenetics not only to figure out which chemicals might endanger public
health, but to find new ways to prevent or treat diseases.

Scientists are just now beginning to figure out normal methylation
patterns in the genome so they can learn what is abnormal, said Karl T.
Kelsey, professor of community heath and pathology at Brown University
in Rhode Island. As a result of this new understanding, epigenetic
therapies have been developed for some types of cancers, and some have
been successful in clinical trials, he said. Unlike traditional cancer
drugs, which kill cells, the new drugs simply change how the cells act.

Research with rats shows that gene-altering chemicals can change
animals' brains-in some cases, in a beneficial way.

Moshe Szyf, a pharmacology and therapeutics professor at McGill
University Medical School in Montreal, found that rats that received
healthy doses of maternal licking as pups grew up to be calmer than pups
who had inattentive mothers. The maternal grooming brought about a
chemical change in the part of the pup's brain that produces stress
hormones, he said.

The rats reared by attentive mothers had different levels of corticoid
gene expression and lower levels of stress hormones than those reared by
inattentive mothers. Szyf found he could cure the stressed rats by
injecting a chemical called TSA into their brains, which reversed the
inappropriate methylation caused by inattentive mothering.

This understanding of epigenetics may lead to new medications for
treating human problems. By using approaches similar to those used in
the rat study, Szyf is hoping to find drugs that will help alleviate
human psychiatric conditions.

Szyf also studied the preserved brains of suicide victims and of people
who died suddenly from causes other than suicide. He found that certain
genes in the suicide victims were methylated, or turned off. In
contrast, those same genes were not methylated in the victims who died
by other means. Abnormal methylation patterns could cause depression in
some people, he said.

Some compounds, such as nickel, chromium and arsenic, are well-known
carcinogens-not because they are toxic to cells but because of their
epigenetic effect, said Max Costa, a New York University professor of
environmental medicine and pharmacology. They increase DNA methylation,
which results in gene silencing and cell transformation and leads to
cancer, he explained.

Researchers at the meeting spent a great deal of time discussing whether
and how to test chemicals for their ability to cause epigenetic changes.

Most researchers there agreed that compounds need to be tested for
epigenetic effects. But practical testing of the 80,000 or so chemicals
in commerce would require rapid screens that would prioritize the
compounds into high, medium, and low-risk groups. Those at high risk for
epigenetic effects could then be subjected to more definitive and
expensive tests.

John M. Greally, associate professor at the Albert Einstein College of
Medicine in New York City, pointed out that no single test is ideal for
detecting epigenetic effects.

"All of the assays have drawbacks," he said. For example, one assay
requires immediate sample processing so it cannot be used on stored
samples.

Nevertheless, many researchers said that testing chemicals for
epigenetic changes can begin soon.

"The fact that we don't know a great deal about this area doesn't mean
it's daunting," said George Daston, research fellow at Procter & Gamble.
"We just need to build on what we have. Microassays already show how
chemical exposures change the gene expression in certain parts of the
genome. The fact that we don't know a lot doesn't mean we can't start
testing quickly."

Birnbaum, who formerly was head of experimental toxicology at the U.S.
Environmental Protection Agency, said regulators and industry don't have
to start from square one.

"We're already marching down this road," said Birnbaum. "The National
Toxicology Program is already talking about including some epigenetic
studies in the program."

The most important public health issue that arises from epigenetics,
Birnbaum told Environmental Health News, is that the current environment
may not be the crucial factor to consider when examining what causes
diseases.

"Asking heart attack victims what they ate this year or last may be far
less important than what they were exposed to in the womb and shortly
after birth," she said.





Deborah L. DeBiasi 
Email:   Deborah.DeBiasi at deq.virginia.gov (NEW!)
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Office of Water Permit Programs 
Industrial Pretreatment/Toxics Management Program 
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