AChE-Independent Phosphoprotein Signaling in an Acute Mouse Model of Gulf War Illness

Details

• Personal Author:
  Boyd JW ; Kelly KA ; Michalovicz LT ; Miller DB ; Miller JV ; Mouch JA ; O'Callaghan JP ; Prince N
• Description:
  Roughly 25-30% of veterans from the 1991 Persian Gulf War suffer from a persistent and amplified form of sickness behavior, classified as Gulf War Illness (GWI). Previous studies investigating GWI have suggested that exposure to organophosphates (OP) in theater, such as the irreversible acetylcholinesterase (AChE) inhibitor and chemical warfare agent, sarin, as well as other pesticides, may have contributed to GWI symptomatology. Additionally, concomitant exposure to high physiological stress in theater has been implicated in the initiation of the GWI phenotype. Traditionally, inhibition of AChE and the subsequent accumulation of acetylcholine (ACh) result in the activation of the cholinergic anti-inflammatory pathway. However, we have shown that the link between GWI and neuroinflammation appears to contradict this effect of AChE inhibitors. Therefore, it is plausible that exposure to OPs both alone and in combination with corticosterone (CORT; used as a physiological stress mimic) may target biomolecules other than AChE to induce the neuroinflammatory effects seen in our validated mouse model of GWI. To further investigate this phenotype, adult male C57BL/6J mice were exposed to CORT in the drinking water for 4 or 7 days. On the 5th or 8th day, mice were exposed to a single dose of a sarin surrogate, diisopropyl fluorophosphate (DFP; 4.0mg/kg, i.p.). To fully evaluate the brain-region specific effects of DFP and CORT+DFP on AChE, ACh concentrations were measured in cortex (CTX), hippocampus (HIP) and striatum (STR) using HILIC UPLC-MS/MS. Mice were euthanized using focused microwave irradiation to ensure rapid inactivation of AChE, as well as endogenous proteases and phosphatases. From these datasets, the alterations of ACh in the brain do not appear to correspond with the exacerbated neuroinflammation induced by CORT+DFP exposure. Therefore, interrogation of potential organophosphorylation targets and aberrant phosphoprotein responses of critical signaling pathways in the STR were conducted. Of the 28 phosphoprotein targets measured using multiplex ELISA, the GWI model (CORT+DFP) had numerous targets with increased phosphorylation over DFP alone (e.g., ERK1/2, GSK3, IkBa, JNK, MEK1), suggesting a need for measuring aberrant early intracellular signaling events to elucidate potential biomolecular drivers of GWI symptomatology. [Description provided by NIOSH]
• Subjects:
  Behavior Enzymes Genetics Hazardous Substances Immune System Insecticides Laboratories Nervous System Occupational Exposure Occupational Health Phosphoric Acids Safety Toxicology

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• Keywords:
  Acetylcholinesterase Analytical Models Behavior Patterns Biological Effects Biological Materials Brain Electrical Activity Brain Function Brain Matter Cell Function Cell Signaling Cellular Effects Cellular Reactions Chemical Warfare Agents Cholinergic Receptors Cholinesterase Inhibitors Chronic Exposure Chronic Inflammation Corticosteroids Dose Response ELISA Enzyme-linked Immunosorbent Assay Enzyme Activity Exposure Assessment Genes Immune Reaction Immune System Laboratory Animals Laboratory Testing Military Personnel Neurotoxic Agents Organic Compounds Organophosphorus Compounds Pesticides Phosphates Physiological Stress Proteins Toxic Effects Toxic Materials

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; OSHA Region 6 ; Texas ; 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:
  162
• Issue:
  1
• NIOSHTIC Number:
  nn:20051280
• Citation:
  Toxicologist 2018 Mar; 162(1):503
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Sarin (CAS RN 107-44-8)
• Federal Fiscal Year:
  2018
• NORA Priority Area:
  Healthcare and Social Assistance ; Transportation, Warehousing and Utilities
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 57th Annual Meeting and ToxExpo, March 11-15, 2018, San Antonio, Texas
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:fedce3461c639e3c0c8f345619828f2a9b34f110d05cfbcdb553c5fac1bd273670a620efa89c333643fd3d50893ee8f4f6cd86e2607d9065bf273e05c3aeac08
• Download URL:
  https://stacks.cdc.gov/view/cdc/211327/cdc_211327_DS1.pdf
• File Type:
  [PDF - 833.17 KB ]