APPENDIX II-AV:
Mix of Chemicals Plus Stress Damages Brain, Liver in Animals and Likely
in Humans
http://www.dukemednews.org/news/article.php?id=7433
Mix of Chemicals Plus Stress Damages Brain, Liver in Animals and Likely in
Humans
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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
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.