The finding, published in the March 17 online version of Nature Genetics, is the first to demonstrate a clear genetic link between neurological disorders and exposure to organophosphate chemicals; the gene is one that scientists had not studied in previous efforts to find connections between these chemicals and disease. Organophosphates include household pesticides as well as deadly nerve gases like sarin.
Dr. Carrolee Barlow, who led the work at the Salk Institute and is now at Merck and Co., Inc., and her team, headed by Christopher Winrow, found in mice that organophosphate exposure inhibited the activity of a gene called neuropathy target esterase, or NTE. This inhibition either killed the mice before birth, or over time led to a range of behaviors very similar to ADHD. Some of the neurological problems also echoed many of the symptoms seen in Gulf War syndrome.
"There have been anecdotal links made between rises in ADHD, Parkinson's disease and other disorders and exposure to pesticides," said Barlow, an adjunct faculty member at the Salk. "There also has been suspicion of a link to Gulf War syndrome. But scientists have been focusing on enzymes that act on acetylcholine neurotransmitters. This study shows that there may indeed be a genetic connection that explains how organophosphates can cause these reactions; it's just not what we assumed it would be."
Barlow's group had originally been looking at how environmental factors immediately affect the nervous system. They found that mice bred to lack the NTE gene died before birth. But the group also found that mice with only one copy of the NTE gene, when exposed to experimental organophosphates and examined over a prolonged period, exhibited behavior similar to ADHD.
The mice with only one NTE copy had a 40 percent decrease in the NTE enzyme produced by the NTE gene. The mice with normal NTE genes also showed ADHD-like behavior, though to a lesser degree, when exposed to organophosphates. The gene is active in parts of the brain controlling movement, including the hippocampus, the cerebellum and the spinal cord.
"NTE is a large gene," said Barlow. "It's possible that we all have slightly different forms of the NTE enzyme, which may explain why some may get ADHD when they're exposed at young ages, and why some may get Gulf War syndrome at a later age, or why some of us have no symptoms at all. It appears to be a case of delayed toxicity, inhibiting the function of NTE."
At the Salk, researcher Matthew Hemming in Professor Stephen Heinemann's laboratory is continuing to work on unlocking the secrets of NTE's activity. The Salk team is working to detail how losing NTE function results in behavioral and neurological changes, as well as focusing on what happens when the gene for NTE is turned off in one part of the brain, but working in other areas.
The Gulf War syndrome is a loosely defined collection of symptoms, ranging from headache and fever to severe forgetfulness and movement disorders. It was first noted after Operations Desert Storm and Desert Shield in 1991, when U.S., Canadian and British military veterans reported more symptoms than soldiers who were not deployed. Its cause is unknown.
The researchers are supported by a $1.5 million grant from the U.S. Department of Defense. Barlow's colleagues on the project include Christopher Winrow, Duane Allen, and, Gary Quistad and John Casida of the University of California, Berkeley.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.