Corticosterone-primed neuroinflammatory response to AChE inhibitors is not related to brain acetylcholine concentration

Details

• Personal Author:
  Kelly KA ; Michalovicz LT ; Miller DB ; Miller JV ; O'Callaghan JP
• Description:
  Roughly 30% of veterans from the 1991 Gulf War (GW) suffer from a persistent and heightened form of sickness behavior, which has been classified as Gulf War Illness (GWI). Previous GWI studies have suggested that exposure to acetylcholinesterase inhibitors (AChEIs) in-theater, such as sarin, a chemical warfare agent and irreversible AChEI, as well as other pesticides and insecticides, may have contributed to the symptomatology of GWI. In addition to exogenous chemical exposure, concomitant high physiological stress in-theater may have contributed to the initiation of the GWI phenotype. While inhibition of AChE leading to the accumulation of acetylcholine (ACh) will activate the cholinergic anti-inflammatory pathway, the exaggerated sickness behavior that is characteristic of GWI has been shown to be associated with neuroinflammation. To investigate the relationship between AChE inhibition and neuroinflammation, we used our previously established mouse model of GWI, which combines an exposure to a high physiological stress mimic, corticosterone (CORT), with GW-relevant AChEIs. Adult male C57BL/6J mice were exposed to CORT (400mg/L) in drinking water for 4 days. On the 5th day, mice were exposed to a single intraperitoneal (i.p.) dose of an AChEI: diisopropyl fluorophosphate (DFP; 4.0mg/kg), an irreversible AChEI and sarin surrogate, chlorpyrifos oxon (CPO; 8mg/ kg), the active metabolite of chlorpyrifos, an irreversible AChEI insecticide used in-theater, and physostigmine (PHY; 0.5mg/kg), a reversible AChEI similar to pyridostigmine bromide, which was used as a prophylactic against nerve agents in-theater. After AChEI exposure, mice were sacrificed and ACh concentrations for cortex (CTX), hippocampus (HIP), and striatum (STR) were determined using hydrophilic interaction liquid chromatography (HILIC) with ultra-performance liquid chromatography (UPLC)-tandem-mass spectrometry (MS/MS). CORT pretreatment ameliorated the DFP-induced ACh increase in HIP and STR but not CTX. These effects were similar for CPO and PHY, but not as pronounced as DFP. qPCR of mRNA biomarkers for neuroinflammation revealed an exacerbated CORT+AChEI response, which does not correspond to ACh measured in the brain. This suggests that GWI may be due to off-target or secondary mechanisms of AChEI exposure via organophosphorylation of unknown biomolecular targets and not AChE inhibition. [Description provided by NIOSH]
• Subjects:
  Adrenal Cortex Hormones Behavior Biomarkers Environmental Exposure Immune System Insecticides Laboratories Nervous System Nervous System Diseases Occupational Health Safety Toxicology

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• Keywords:
  Acetylcholinesterase Analytical Models Analytical Processes Behavior Patterns Biological Warfare Agents Brain Function Brain Matter Chlorpyrifos Cholinesterase Inhibitors Cholinolytic Agents Corticoids Exposure Assessment Exposure Levels Health Effects Immune Reaction Immune System Laboratory Animals Laboratory Testing Liquid Chromatography Mass Spectrometry Military Personnel Models Neurological Disorders Neurological Reactions Neurophysiological Effects Neurotoxic Agents Organophosphorus Insecticides Physiological Stress Prophylaxis Sarin

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; 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:
  156
• Issue:
  1
• NIOSHTIC Number:
  nn:20049415
• Citation:
  Toxicologist 2017 Mar; 156(1):176
• CAS Registry Number:
  (-)-Physostigmine (CAS RN 57-47-6) ; Chlorpyrifos (CAS RN 2921-88-2) ; Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Pyridostigmine bromide (CAS RN 101-26-8) ; Sarin (CAS RN 107-44-8)
• Federal Fiscal Year:
  2017
• NORA Priority Area:
  Healthcare and Social Assistance ; Transportation, Warehousing and Utilities
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 56th Annual Meeting and ToxExpo, March 12-16, 2017, Baltimore, Maryland
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:6788674815ba3f8639227c799cb1965a4900a1cb09da4cea49ad92415964c6a158db867d83ed56b7aef8bb388a82e23931c84a6a1940dc7a03f9a48262720828
• Download URL:
  https://stacks.cdc.gov/view/cdc/203864/cdc_203864_DS1.pdf
• File Type:
  [PDF - 945.11 KB ]