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Mix of Chemicals Plus Stress Damages Brain, Liver in Animals and Likely in Humans

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Duke Health News 919-660-1306

DURHAM, N.C. -- Stress is a well known culprit in disease,
but now researchers have shown that stress can intensify the
effects of relatively safe chemicals, making them very harmful
to the brain and liver in animals and likely in humans, as
well.

Even short-term exposure to specific chemicals -- just 28
days -- when combined with stress was enough to cause
widespread cellular damage in the brain and liver of rats, said
Mohamed Abou Donia, Ph.D., a Duke pharmacologist and senior
author of the study.

Results of the study were published in the Feb. 27, 2004,
issue of the Journal of Toxicology and Environmental
Health.

Abou Donia's study was designed to reproduce the symptoms of
Gulf War Syndrome, a disorder marked by chronic fatigue, muscle
and joint pain, tremors, headaches, difficulties concentrating
and learning, loss of memory, irritability and reproductive
problems. The Gulf War Syndrome symptoms have been difficult to
explain because veterans outwardly appear healthy and normal,
said Abou Donia. Likewise, the chemically exposed animals in
Abou Donia's studies looked and behaved normally.

But a decade of neurologic research has revealed widespread
damage to the brain, nervous system, liver and testes of rats
exposed to 60 days of low-dose chemicals -- the insect
repellant DEET, the insecticide permethrin, and the anti-nerve
gas agent pyridostigmine bromide. These are the same drugs that
the soldiers received during the 1990 - 1991 Persian Gulf War,
and Abou Donia's rats were exposed to the same levels -- in
weight adjusted doses -- as the soldiers were reportedly
given.

Now, Abou Donia has demonstrated that the combination of
stress and short-term exposure to chemicals (28 days) can
promote cellular death in specific brain regions and injury to
the liver. Moreover, the chemical trio combined with stress
caused damage to portions of the brain where its protective
blood-brain barrier was still intact.

The latter finding suggests that the chemicals permeated the
protective barrier in one region, then leaked into other
regions of the brain where the barrier remained intact. The
ability of chemicals to leak from one area of the brain to
another holds the potential for much greater damage to occur to
the entire brain.

Brain regions that sustained significant damage in this
study were the cerebral cortex (motor and sensory function),
the hippocampus (learning and memory) and the cerebellum (gait
and coordination of movements). Abou Donia's earlier studies
demonstrated severe damage to the cingulate cortex, dentate
gyrus, thalamus and hypothalamus.(The thalamus is the major
relay for visual and auditory information going to the cortex
and is also responsible for subjective feelings. The
hypothalamus regulates metabolism, sleep and sexual activity,
as well as control of emotions.)

Abou Donia's team found a significant number of dead or
dying brain cells in all of these brain regions, as well as
major alterations to brain chemicals that are necessary for
learning and memory, muscle strength and body movement. Stress
alone caused little or no brain injury in the rats, nor did the
three chemicals given together in low doses for 28 days.

"But when we put the animals under moderate stress by simply
restricting their movement in a plastic holder for five minutes
at a time every day, the animals experienced enough stress that
it intensified the effects of the chemicals dramatically," said
Abou Donia.

Soldiers in the Gulf War were likely under stress 24 hours a
day for weeks or months at a time, a scenario which could
explain the origins of their diverse physical and cognitive
complaints, said Abou Donia.

"The brain deficits we found in rats reside in specific
areas of the brain that we can't measure in living humans,"
said Abou Donia. "This is why the deficits are so difficult to
assess clinically and why animal studies are so critical to
understanding the cellular damage."

In addition to brain injuries, the Duke study found
unexpected damage to the liver, including swollen cells,
congested blood vessels and abnormal fatty deposits that
diminish the liver cells' function. Liver cells also showed
reduced activity of an important enzyme -- BuCHE -- that helps
rid the body of some toxic substances. Neither stress by itself
nor chemicals alone had any impact on BuCHE levels, but the
combination did.

Such damage to the liver can reduce its ability to rid the
body of toxic substances -- its primary function as a vital
organ. And, the less effectively the liver filters out toxic
substances, the more the chemicals can concentrate in the brain
and nervous system, he added.

Finally, the study showed that stress plus chemicals
increased the amount of destructive molecules in the brain
called reactive oxygen species -- also known as oxygen free
radicals. Reactive oxygen species are produced by the body as
it metabolizes various substances in the presence of
oxygen.

Reactive oxygen species attack DNA, RNA and proteins,
causing cellular and membrane damage. Normally, the body
removes these chemicals from the body and the brain. But
excessive production of reactive oxygen species can overwhelm
the body's ability to dispose of them.

"In our study, there was an increase in reactive oxygen
species. We think that either the three chemicals and stress
directly produce these free radicals, or the chemicals impede
the body's ability to get rid of them," said Abou Donia.

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