Genetic-Based, Differential Susceptibility to Exposure to Combined Organophosphate and Increased Glucocorticoid in a Mouse Model of Gulf War Illness

Details

• Personal Author:
  Ashbrook D ; Jones BC ; Lu L ; Miller DB ; O'Callaghan JP ; Zhao W
• Description:
  In 1990-1991, the USA sent 700,000 troops to the first Gulf War. Approximately 25% of the deployed soldiers developed a chronic multisymptom illness with many features of "sickness behavior." This disorder now has been termed Gulf War Illness (GWI) and, remarkably, for those so afflicted, most have symptoms that persist to this day, nearly 30 years later. The cause of GWI has been thought to center on a variety of exposures that occurred in theater, including organophosphate nerve agent (sarin) and insecticides (e.g. chlorpyrifos). We have developed an animal model of GWI that combines exposure to corticosterone as a physiological stressor mimic with diisofluorophosphate (DFP) (as nerve agent analogue) to mirror some of the exposure/conditions that occurred in theater. The model was developed in the C57BL/6 (B6) mouse strain. The question raised was while 25-30% of the troops became ill, what about those who did not -- all else being equal? The B6 mouse strain is one of the founders of a large panel of recombinant strains (BXD) derived from crossing with the DBA/2 (D2) strain. The mouse model of individual differences in susceptibility to combined OP and high circulating glucocorticoid (corticosterone -- CORT) is to test the D2 strain and several of the BXD strains (and both sexes). The protocol involved adding corticosterone to the drinking water (20mg%) of the mice for 7 days followed on the 8th day by injection of diisopropyl-flurophosphate (DFP, 4mg/kg) followed 6h later by euthanasia and harvesting the frontal cortex. The index for neuroinflammation was change in expression of proinflammatory cytokine genes, IL1beta, IL6 and TNFalpha. The results showed that the D2 mice were less sensitive to CORT+DFP than the B6 and that there were large differences among 30 of the BXD strains. We then performed genome-wide mapping of the IL1beta results and found a significant marker (quantitative trait locus) on distal chromosome 7. Searching that area on Chromosome for possible candidate genes, we identified Spondin 1 as candidate. The gene is cis-regulated and its expression is significantly correlated (r=0.76, p<0.01) with the expression of IL1beta expression under exposure to CORT+DFP. These results show that susceptibility to GWI likely has a genetic component and we will show that further testing of the BXD mice will produce more candidates. We can then identify biochemical pathways that differ and possibly develop treatments and means of prevention. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Behavior Environmental Exposure Genetics Immune System Insecticides Laboratories Nervous System Nervous System Diseases Occupational Health Phosphoric Acids Safety Toxicology

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• Keywords:
  Analytical Models Biochemical Markers Brain Matter Cellular Reactions Chlorpyrifos Corticoids Corticosteroids Cytokines Dose Response Exposure Assessment Exposure Levels Gene Expression Genes Genetic Factors Immune Reaction Laboratory Animals Laboratory Testing Military Personnel Mixed Exposures Neurological Disorders Neurotoxic Agents Organophosphorus Compounds Phosphates Physiological Stress Sarin

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; OSHA Region 3 ; OSHA Region 4 ; Tennessee ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  168
• Issue:
  1
• NIOSHTIC Number:
  nn:20054979
• Citation:
  Toxicologist 2019 Mar; 168(1):274
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2) ; Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Sarin (CAS RN 107-44-8)
• Federal Fiscal Year:
  2019
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 58th Annual Meeting and ToxExpo, March 10-14, 2019, Baltimore, Maryland
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:700d1e9387a5f30488ba2564d5e7d8928390f365351d6c523da905bb37a3827187dccbd6a980408482ed573e37d55d1a17873921f29df7fe1c9f8f23deca89b1
• Download URL:
  https://stacks.cdc.gov/view/cdc/217385/cdc_217385_DS1.pdf
• File Type:
  [PDF - 865.56 KB ]