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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