Validating a Model of Gulf War Illness: Chronic Exposure to Glucocorticoids Primes the Neuroinflammatory Response to Diisopropyl Fluorophosphate Resulting in Long-Lasting Sensitivity to Subsequent Challenges

Details

• Personal Author:
  Kelly, K.
• Description:
  Gulf War Illness (GWI) is a multi-symptom disorder diagnosed by symptoms including persistent headaches, chronic fatigue, memory loss, confusion, skin and gastrointestinal problems. These features are characteristic of persistent sickness behavior, which is known to result from underlying neuroinflammation. Chronic exposure to corticosterone (CORT), at levels associated with high physiological stress, can prime the CNS to mount an exacerbated neuroinflammatory response, indicated by an increase in proinflammatory cytokines/chemokines, following systemic exposure to challenge. By mimicking the stresses of war with exogenous CORT (200 mg/L 0.6% EtOH in drinking water) for 7 days prior to exposure to sarin surrogate acetylcholinesterase inhibitor (AChEI), diisopropyl fluorophosphate (DFP; 4 mg/kg, i.p.), heightened neuroinflammatory responses were observed without astrogliosis or neurodegeneration. While these observations recapitulated early symptoms of GWI, the essential pathobiology of this illness is persistence of heightened responses to external stimuli for the 20+ years after the instigating exposures. Here, we employed episodic exposure to CORT in drinking water to emulate episodic stress incurred by ill veterans following their exposures to AChEI agents in theater. As the GWI phenotype is punctuated by symptom flare-ups, systemic exposure to lipopolysaccharide (LPS - a bacterial mimic; 0.5 mg/kg, s.c.), was used to challenge the GWI phenotype. While CORT pretreatment primes the neuroinflammatory response to produce augmented LPS-induced inflammation, a single dose of DFP significantly exacerbated this effect. Using a comprehensive survey of molecular markers, blood cytokine expression profiles of ill veterans compared to our GWI mouse model revealed a significant overlap of the phenotype between man and mouse. This correlation supports the hypothesis that exposure to sarin, or a similar AChEI, in theater served as a major precipitating factor for the development of GWI. Overall, we demonstrated that a paradigm of CORT in the drinking water with a single DFP exposure followed by episodic CORT instigates a primed neuroinflammatory phenotype similar to that of Gulf War Illness. Together, these data suggest that GWI is a chronic, stressor primed, neuroinflammatory condition. Description provided by NIOSH
• Subjects:
  • Chronic Disease
  • Inflammation
  • Military Health
  • Military Personnel
  • Nervous System
  • Nervous System Diseases
  • Neuroinflammatory Diseases
  • Occupational Health
  • Persian Gulf Syndrome
  • Safety
  More +
• Keywords:
  • Military personnel; Neurological disorders; Cytokines; Chronic inflammation; Physiological stress; Biomarkers; Chronic exposure
• Source:
  Toxicologist 2025 Mar; 204(S1):57
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Philadelphia Region OSHA ; 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:
  2 pdf pages
• Volume:
  204
• NIOSHTIC Number:
  nn:20071571
• Federal Fiscal Year:
  2025
• NORA Priority Area:
  Services
• Peer Reviewed:
  False
• Download URL:
  https://stacks.cdc.gov/view/cdc/259346/cdc_259346_DS1.pdf
• File Type:
  [PDF - 258.82 KB]
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:f5d454abbebca2dc2fa5b3aa0bb6848751201ce727149c389a0da1d677c435dc49a7db227571921ce50dd54c571ff1b853b3327a962b38bc1389c4a00b53140c