Mix of Chemicals, Stress Likely Cause Damage in Humans

Stress is a well known culprit in disease, but now researchers at Duke University are finding that stress can intensify the effects of relatively safe chemicals, making them very harmful to the brain and liver in animals with damage 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 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, such as the insect repellant DEET, the insecticide permethrin, and the anti-nerve gas agent pyridostigmine bromide. These are the same chemicals that the soldiers were exposed to 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 reportedly received.

The researchers found 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 in rats, and they speculated that similar damage could occur in humans. 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). The research 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.

"When we put the animals under moderate stress by simply restricting their movement in a plastic holder for 5 minutes at a time every day, the animals experienced enough stress that it intensified the effects of the chemicals dramatically," noted Abou Donia.

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.

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