Chronic glucocorticoid and nerve agent DFP exposures produce a neuroinflammatory model of Gulf War Illness without neurodegeneration

Details

• Personal Author:
  Kelly KA ; Lasley SM ; Miller DB ; O'Callaghan JP ; Revitsky AR
• Description:
  Gulf War Illness (GWI) is a persistent, multi-symptom disorder with features characteristic of sickness behavior. Several exposures have been hypothesized as triggers of the recurring/chronic symptoms associated with GWI, including exposure to the nerve agent sarin that resulted from munition detonations at multiple sites. Here, we investigated the effects of exposure to the sarin surrogate, diisopropyl fluorophosphate (DFP), on peripheral and CNS inflammation. Male C57BL/6J mice were pretreated with corticosterone (CORT) in the drinking water for 7 days to mimic high physiological stress, followed 1 day later by DFP (4 mg/kg, i.p.) exposure to model GWI. DFP exposure alone did not change inflammatory markers in serum and liver, however, increases in expression of inflammatory cytokines/chemokines were found in the brain. Further, CORT exposure for 7 days prior to exposure to DFP greatly augmented inflammatory responses in the brain. Pretreatment with anti-inflammatory antibiotic, minocycline, attenuated this neuroinflammatory effect. Subsequent investigation of neurodegeneration as indexed by GFAP protein content revealed no treatment-related increases following exposure to DFP or CORT+DFP. Immunohistochemical data revealed small, region-specific (e.g. hippocampus CA-1) changes in microglia and astrocyte morphology (Iba-1 and GFAP, respectively); and no neurodegeneration was seen with silver or Fluoro-Jade B assessments of damage. These results suggest increases in neuroinflammation, findings consistent with sickness behavior, may be characteristic of GWI, potentially induced by exposure to nerve agents, and can be exacerbated by exposure to chronic stress conditions (e.g., extreme temperatures, daily threat to safety/survival). While exposure to both stress hormones and nerve agents may be enough to produce increases in neuroinflammation, which likely contribute to sickness behavior seen in GWI, these conditions do not produce neural damage. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Anti-Bacterial Agents Behavior Biological Warfare Agents Chronic Disease Endocrine System Environmental Monitoring Immune System Laboratories Mental Disorders Nervous System Nervous System Diseases Nervous System Disorders Occupational Health Safety Toxicology

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• Keywords:
  Antibiotics Behavioral-disorders Biological-warfare-agents Brain-damage Central-nervous-system-disorders Chronic-inflammation Clinical-symptoms Corticoids Dose-response Exposure-assessment Histochemical-analysis Hormones Immune-reaction Immunochemistry Laboratory-animals Laboratory-testing Mental-illness Military-personnel Neurotoxicity Physiological-stress Pretreatment Stress

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; Illinois ; OSHA Region 3 ; OSHA Region 5 ; OSHA Region 9 ; 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:
  144
• Issue:
  1
• NIOSHTIC Number:
  nn:20045994
• Citation:
  Toxicologist 2015 Mar; 144(1):456
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4)
• Federal Fiscal Year:
  2015
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 54th Annual Meeting and ToxExpo, March 22-26, 2015, San Diego, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:dcfa59faa1645d35cb9f7db23f2f435b8e44030d6f34d8432f2159da1ec32a702a30fca802aaf12078a6326ab689a6430794145740568cd2400c54bd4eabb55a
• Download URL:
  https://stacks.cdc.gov/view/cdc/201193/cdc_201193_DS1.pdf
• File Type:
  [PDF - 228.38 KB ]