Behavioral and Histological Evidence of a Neuroimmune Basis for Gulf War Illness

Details

• Personal Author:
  Fornal C ; Kelly K ; Lasley S ; Michalovicz L ; Miller D ; O'Callaghan J
• Description:
  Chronic exposure to the glucocorticoid, corticosterone (CORT), at levels associated with high physiological stress, has been shown to prime the neuroimmune response to neurotoxic exposures and systemic inflammation, significantly increasing the expression of proinflammatory cytokines/chemokines following exposure. Gulf War Illness (GWI) is a multi-symptom, neuroimmune-based disorder that presents with features characteristic of persistent sickness behavior. Using a preclinical mouse model of GWI, we have found that chronic exposure to the stress hormone corticosterone (CORT; 200-400 mg/L) in the drinking water for 7 days exacerbated the initial neuroinflammatory response to the sarin surrogate diisopropylfluorophosphate (DFP; 4 mg/kg, i.p.). A more recent study using this exposure protocol has found that CORT+DFP exposed animals exhibit cognitive impairment in the Novel Object Recognition Test with decreased discrimination of the novel versus familiar object. However, this acute exposure model is more representative of the veterans' time in theater, and those suffering with GWI are nearly 30 years removed from their tours of duty. Thus, a more extended duration animal model is necessary. Our model of GWI at 5 weeks after the initial CORT+DFP event, constituting periodic administration of CORT for 7 days every other week and a subsequent systemic immune challenge with the bacterial mimic lipopolysaccharide (LPS; 0.25-0.50 mg/kg, s.c.) mimics the long-term illness and 'flare up' of symptoms as is reported in GWI. This longer CORT regimen produced signs of decreased cognition in the Novel Object Location Test, signified by CORT+DFP+LPS animals less able to distinguish the displaced versus familiar object. This paradigm reveals a further exacerbation of neuroinflammatory markers and emergence of activated microglia in key brain areas including hippocampus and cortex that affects behavior for at least 12 days after the last LPS dose. Together, these data provide additional support that GWI is a chronic, stressor-primed, neuroinflammatory condition with adverse long-term neurobiological and behavioral outcomes. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Behavior Endocrine System Environmental Exposure Immune System Laboratories Lipids Nervous System Nervous System Diseases Occupational Exposure Occupational Health Safety Toxicology

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• Keywords:
  Analytical Models Behavior Patterns Brain Function Chronic Exposure Cognitive Function Corticoids Corticosteroids Cytokines Dose Response Exposure Assessment Exposure Levels Hormones Immune Reaction Immunologic Disorders Laboratory Animals Laboratory Testing Lipopolysaccharide Military Personnel Neurological Disorders Neurotoxic Agents Physiological Stress Stress

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Illinois ; Maryland ; OSHA Region 3 ; OSHA Region 5 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  83
• Volume:
  168
• Issue:
  1
• NIOSHTIC Number:
  nn:20054910
• Citation:
  Toxicologist 2019 Mar; 168(1):83
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4)
• 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-512:634568927a3fd205288ccf3a1057fc69e7aa2cae8c1083c53bff619870b269a22146d66f59f97c99b1d28ec74babaae4543898f4b3c33af2f6d5eead9b0053d3
• Download URL:
  https://stacks.cdc.gov/view/cdc/217321/cdc_217321_DS1.pdf
• File Type:
  [PDF - 860.59 KB ]