- Analysis of Paraoxonase Status among U.S. Navy Gulf War Veterans with Increased Postwar Symptoms, Psychological Morbidity and Medical Conditions
- Structural MRI and Cognitive Correlates in Pest-Control Personnel from Gulf War I
- Novel Pharmacological Approaches for Treatment of Neurotoxicity Induced by Exposure to Depleted Uranium
Analysis of Paraoxonase Status among U.S. Navy Gulf War Veterans with Increased Postwar Symptoms, Psychological Morbidity and Medical Conditions
Posted December 21, 2009
Lt Col Christopher J. Phillips, MD, MPH, Naval Health Research Center, San Diego, CA
Gulf War Illness (GWI) is a complex of chronic multisymptom health problems that affects 175,000 to 210,000 of 697,000 (at least one fourth) of the U.S. veterans who served in the 1990-1991 Gulf War. The multiple concurrent symptoms typically include a combination of memory and concentration problems, chronic headaches, widespread pain, unexplained fatigue, chronic digestive difficulties, respiratory symptoms, and skin abnormalities not explained by established medical diagnoses or standard laboratory tests. No effective treatments have been identified for Gulf War Illness and few veterans have reportedly recovered. There is increasing evidence suggesting that the higher rate of GWI in Gulf War Veterans (GWV) can be associated with neurotoxic exposures of GWV to organophosphate(OP) and carbamate acetyl cholinesterase inhibitors (AChEis) such as pyridostigmine bromide (PB), pesticides, and nerve agents. PB pills were given to protect deployed troops from the potential effects of nerve agents.
US Navy Seabees, both non-deployed and those deployed in the Gulf War participated in a 1994 study by answering extensive questionnaires about war time exposures, postwar symptoms, and also by providing sera. The study reported a higher rate for 35 out of 41 symptoms among GW deployed Seabees versus non-deployed Seabees. However, neither the 1994 study nor a large (n=11,868) Seabee survey study in 1999 could establish a clear link between environmental exposures and post war symptoms.
Prior studies have reported that differences in PON1 enzyme activity may be associated with Gulf War illnesses, or perhaps more generally with service in the Gulf War. Serum PON1 has been reported to be polymorphic as an Arg192 isoform (PON1R192) and/or a Gln192 isoform (PON1Q192) in human populations. The hydrolysis activity (detoxification activity) of PON1 isoforms varies among different organophosphorous compounds as paraoxon (POX) and diazoxon (DZO).
Lt Col Christopher J. Phillips, MD, MPH, from Naval Health Research Center, received a Department of Defense Fiscal Year 2006 Gulf War Illness Research Program (GWIRP) Exploration - Hypothesis Development Award to investigate PON1 status, defined by the phenotype (enzyme activity) and genotype (PON1-192 Q/Q; Q/R; R/R) and associations with the frequency of self-reported symptoms of the 1994 US Navy Seabees study cohort classified as GWI cases.
Of the 294 US Navy deployed Seabees who participated in the 1994 study, 51 (17%) met the GWI case definition. PON1 status was determined using a validated spectrophotometric assay to study hydrolysis activity of serum or plasma PON1 for substrates such as diazoxon and paraoxon. PON1-192 isoforms of the deployed Seabees who met the case definition of GWI were determined to be QQ (41%), QR (27%), and RR (31%). Adjusted model results indicated that the RR PON1 genotype correlated with the highest odds (OR=4.0) for meeting the GWI case definition. Also, taking PB pills, exposure to burning jet fuel in tent heaters, and exposure to petroleum spraying increased the odds of developing GWI among the deployed Seabees, while self-reported exposure to pesticides did not increase the odds of having GWI.
Pesticides were widely used during the 1991 Gulf War (GW) to protect troops from infectious disease-carrying insects. During their deployment, GW veterans were exposed to pesticides where they worked, slept, and ate. One class of these pesticides, organophosphates, is known to produce chronic neurological symptoms at sufficient exposure levels by inhibiting the enzyme acetylcholinesterase (AChE). Exposure to AchE-inhibiting organophosphate pesticides and anti-nerve gas pills (pyridostigmine bromide [PB]) has long been a suspected cause for the persistent health complaints of GW veterans. Drs. Kimberly Sullivan and Maxine Krengel, of Boston University, used a Fiscal Year 2006 Gulf War Illness Research Program Investigator-Initiated Research Award to follow up on their earlier work (also supported by the CDMRP) with pesticide applicator personnel who also took PB tablets. Drs. Sullivan and Krengel will analyze structural brain MRIs with a highly exposed subgroup of this cohort and record volumetric measurements of key brain areas including total gray matter, white matter, and ventricle volumes. This follow-up neuroimaging study will evaluate the combination of exposures to AChE inhibitors as factors in the expression of GWI veterans' continued health symptoms. In addition, this study could provide a biomarker of brain pathology in these veterans if structural brain differences are identified and can be correlated with functional differences seen on cognitive test measures. Knowledge of these relationships will be useful in identifying objective indicators of pathology that distinguish ill from healthy Gulf War veterans and may help identify potential avenues for treatment.
Depleted Uranium (DU) is a byproduct of natural uranium whose radioactivity is roughly half that of the natural product. According to the World Health Organization, DU is used as counterweights in aircraft, radiation shields in medical devices, and as containers to transport radioactive materials. The military uses DU in its armor plating and in armor piercing rounds to take advantage of its high density. Unfortunately, a number of soldiers who served in the Gulf War have presented with neurologic illnesses for which the unknown long-term implications of DU exposure cannot be ruled out. In an effort to relieve the suggested neurotoxicity caused by exposure to DU, Dr. Stephen Lasley of the University of Illinois at Chicago proposes the long-term administration of a free radical trapping agent and/or an NMDA receptor antagonist to reduce DU neurotoxicity in Gulf War Veterans.
Dr. Lasley received a fiscal year 2006 Investigator-Initiated Research Award through the Gulf War Illness Research Program to study novel pharmacological approaches for the treatment of neurotoxicity induced by chronic exposure to DU. Using an animal model of DU exposure, Dr. Lasley's research aims to determine the ability of drug therapies to reduce the effects DU has on glutamate neurotransmitter function and to assess biochemical markers related to oxidative stress in the hippocampal tissue of rats.
Currently, Dr. Lasley's research is under way as his team continues to monitor the animals and collect raw data for analysis.
Vietti KRN and Lasley SM. 2007. Stimulus-evoked glutamate release is diminished by acute exposure to uranium in vitro. Neurotoxicol Teratol 29:607-612.