Exploration of the Gulf War Illness phenotype in a mouse model challenged with LPS at long term time points

Details

• Personal Author:
  Kelly KA ; Locker AR ; Michalovicz LT ; Miller DB ; O'Callaghan JP
• Description:
  Chronic exposure to the glucocorticoid, corticosterone (CORT), at high physiological stress levels, can prime the CNS to release proinflammatory cytokines following exposure to neurotoxic exposures and systemic inflammation. Such neuroinflammatory events are associated with sickness behavior. Gulf War Illness (GWI) is a multi-symptom disorder characterized by persistent headaches, chronic fatigue, muscle pain, memory loss, confusion, gastrointestinal problems, and rashes, features also characteristic of persistent sickness behavior. Recently we found that, of the multiple exposures soldiers faced in the 1991 Gulf War theatre, two produced exacerbated neuroinflammation in mice. By mimicking the stresses of war with high physiologic exposure to CORT (200 mg/L 0.6% EtOH drinking water) over 7 days followed by sarin gas exposure with surrogate acetylcholinesterase inhibitor, diisopropyl fluorophosphate (DFP; 4 mg/kg, i.p.), we found heightened neuroinflammatory responses without evidence of astrogliosis or neurodegeneration 6 to 72 hours after DFP exposure. While these observations recapitulated the early symptoms of GWI, the essential pathobiology of GWI is the persistence of heightened responses to external stimuli for the past 20+ years. Here we employed episodic exposure of CORT in the drinking water of C57Bl6/J male mice for up to 180 days (CORT drinking water for 4 or 7 days every other week) to emulate episodic stress incurred by ill veterans following their exposures to multiple agents in theater, including sarin, 2 decades ago. Systemic exposure to LPS, at sub- and neuroinflammatory doses, were used to challenge the GWI phenotype (0.5 or 2 mg/kg, s.c., respectively). Our results show that successive waves of CORT provide a priming of the neuroinflammatory response to LPS, and that DFP (single exposure on the last day of the first CORT treatment) can exacerbate this effect. Thus, confirming this mouse model to produce a similar phenotype as that seen in soldiers diagnosed with GWI. Interestingly, we found that while 4 days of CORT in the drinking water is sufficient to produce an exacerbated neuroinflammatory response to LPS, that successive waves of CORT in 7 day, but not 4 day, exposures, every other week for 90 days produces a synergistic priming of the CNS to greatly augment the neuroinflammatory response to LPS. Together, these data suggest that GWI is a chronic, stressor primed, neuroinflammatory condition. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Animals Behavior Biomarkers Bromides Immune System Laboratories Nervous System Occupational Health Phosphoric Acids Safety Toxicology

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• Keywords:
  Acetylcholinesterase Behavior Patterns Brain Function Brain Matter Cell Damage Cell Function Cellular Reactions Central Nervous System Central Nervous System Disorders Cholinesterase Inhibitors Chronic Inflammation Corticoids Corticosteroids Cytokines Immune Reaction Immune System Laboratory Animals Military Personnel Neurological Reactions Neurological System Neurotoxic Agents Neurotoxic Effects Neurotoxicity Phosphates Physiological Stress Post-traumatic Stress Disorder Proteins PTSD Stress Stress-related Illnesses

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Louisiana ; OSHA Region 3 ; OSHA Region 6 ; 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:
  50
• Volume:
  150
• Issue:
  1
• NIOSHTIC Number:
  nn:20047602
• Citation:
  Toxicologist 2016 Mar; 150(1):50
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Pyridostigmine bromide (CAS RN 101-26-8) ; Sarin (CAS RN 107-44-8)
• Federal Fiscal Year:
  2016
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 55th Annual Meeting and ToxExpo, March 13-17, 2016, New Orleans, Louisiana
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:ab9921426dcb017b54d8f0170320ff1bd075524c9ee26452ca1b0383f83efdb2456fe93f79954397a8d670f9398f30a2ea45765e87c5ad26650b788e55948853
• Download URL:
  https://stacks.cdc.gov/view/cdc/202617/cdc_202617_DS1.pdf
• File Type:
  [PDF - 442.22 KB ]