Chronic High Physiological Stressor Mimic, Corticosterone, Primes the Neuroinflammatory Response in Cortex to Dermal Sulfur Mustard Exposure: A Potential Contribution to Initiation of Gulf War Illness

Details

• Personal Author:
  Billig B ; Felton C ; Kelly K ; Michalovicz Gill L ; O'Callaghan JP ; Yilmaz A
• Description:
  Background and Purpose: Nearly a third of veterans from the 1991 Gulf War returned with a multi-symptom disorder characterized by debilitating fatigue, cognitive dysfunction, chronic widespread pain, gastrointestinal distress, respiratory problems, skin abnormalities, and other symptoms. Taken together with deployment at that time, this disorder is now known as Gulf War Illness (GWI). The symptoms of GWI also are consistent with features of chronic sickness behavior, the underlying basis of which is neuroinflammation. Many wartime exposures have been proposed to serve as the instigating event for GWI including pesticides, nerve agent prophylactic, oil well fires, vaccinations, sand and dust particles, and chemical and biological weapons. While the potential for organophosphate nerve agent exposures has received the most attention with respect to GWI, due to their known neurological effects, it also is believed that Iraq was in possession of additional chemical weapons, including mustard agents. In our initial studies, we focused on exposure to organophosphate compounds such as the nerve agent sarin, as well as chlorpyrifos and dichlorvos pesticides. We found that combing these agents with the rodent stress hormone, corticosterone (CORT), as a stressor surrogate, results in marked and persistent neuroinflammation in mice and rats. We not that there is evidence of similar symptomology after sulfur mustard exposures. Mustard agents can cause acute toxicity to the nervous, respiratory, cardiac, dermal, and digestive systems with chronic conditions lasting many years after exposure. Methods: Here, we have used our established chronic CORT priming regimen (7 days of 200 mg/L 0.6% EtOH in the drinking water) prior to an acute (4-8 min) dermal sulfur mustard exposure in adult male C57BL/6J mice. Tissues were collected at 6- and 24-hours post-mustard exposure with hippocampus and cortex brain areas evaluated for inflammatory cytokine mRNA expression. Results: Results revealed significant (% or fold range) increases in TNFa, C-C motif chemokine ligand 2 (CCL2), and IL-1β in the cortex of CORT + sulfur mustard mice at 6 hours post-exposure, as well as a significant increase in the astrocyte marker, glial fibrillary acidic protein (GFAP), mRNA 6 hours after CORT + sulfur mustard exposure in the cortex; these changes resolved by 24 hours. Additionally, no significant changes in mRNA expression were measured in the hippocampus at either 6 or 24 hours after sulfur mustard exposure. Conclusions: These initial results suggest that dermal sulfur mustard exposure is capable of producing CORT-primed neuroinflammatory responses similar to what has been previously observed in our organophosphate-based GWI model. Thus, exposure to non-organophosphate nerve agents like sulfur mustard, particularly in combination with stress, may have the potential to develop the underlying neuroimmune dysfunction that has been associated with GWI pathology and warrants further study. [Description provided by NIOSH]
• Subjects:
  Fatigue Insecticides Occupational Health Safety
• Keywords:
  Chemical Warfare Agents Chronic Inflammation Military Personnel Neurological Diseases Pesticides Stress
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; 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:
  198
• NIOSHTIC Number:
  nn:20069343
• Citation:
  Toxicologist 2024 Mar; 198(S1):332
• Federal Fiscal Year:
  2024
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 63rd Annual Meeting & ToxExpo, March 10-14, 2024, Salt Lake City, Utah
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:8cc183825d742278453a738b384b9a77b5b7dc9e199e5c8a9a0836a71382585eec620a1b735df6950fd43dc68b5a3a97e36abd05001fdabab1a986ff48c41bba
• Download URL:
  https://stacks.cdc.gov/view/cdc/207841/cdc_207841_DS1.pdf
• File Type:
  [PDF - 539.42 KB ]