Chronic Glucocorticoid Exposure Primes the Neuroinflammatory Response to Nerve Agent Sarin

Details

• Personal Author:
  Kelly KA ; Michalovicz L ; O'Callaghan JP
• Description:
  Chronic exposure to the glucocorticoid corticosterone (CORT), at levels associated with high physiological stress, can exacerbate CNS proinflammatory responses to neurotoxic insults in animal models. Persistent sickness behavior, a prominent component of Gulf War Illness (GWI), is associated with neuroinflammation. Veterans of the 1991 GW were exposed to the stresses of war, being prophylactically treated with the reversible acetylcholinesterase (AChE) inhibitor pyridostigmine (PB), organophosphate pesticides chlorpyrifos (CPO) and dichlorvos (DDVP) and potentially the nerve agent sarin. We have previously shown CORT exacerbation of the neuroinflammatory response to CPO, DDVP, and the sarin surrogate diisopropyl fluorophosphate (DFP). Here, we confirm that sarin exposure also causes a neuroinflammatory response that is exacerbated by chronic CORT pretreatment. CORT (200 ug/mL in 0.6% EtOH) was given in the drinking water for 1 week prior to sarin administration at an LD20 dose (0.1 mg/kg, s.c.) on day 8. Animals were euthanized at 6 hours and brains were dissected and then frozen for RNA and protein analysis. RNAseq analysis of cortex revealed 1535 genes that were significantly up-regulated in the CORT+sarin group. Of these, 211 were significantly greater than sarin alone. These 211 genes were interrogated with DAVID to find GO terms which included cytokine production, MAP kinase phosphatase activity, and cytokine binding. Kegg pathways include: cytokine-cytokine receptor interaction, Jak- STAT signaling pathway, MAPK signaling pathway, and hematopoietic cell lineage. The neuroinflammatory response was further confirmed with elevated pSTAT3 protein by ELISA and elevated neuroinflammatory cytokines and chemokines mRNA (TNFalpha, IL6, CCL2, IL1beta, LIF, and OSM) by qPCR. Together these findings confirm those we have previously shown with sarin surrogate, DFP and provide additional support for the hypothesis that GWI is a chronic, stressor-primed, neuroinflammatory condition potentially instigated by the combined exposures to stressors and irreversible AChE inhibitors. [Description provided by NIOSH]
• Subjects:
  Behavior Blood Environmental Exposure Immune System Insecticides Laboratories Nervous System Nervous System Diseases Occupational Health Organophosphates Phosphoric Acids Safety Toxicology

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• Keywords:
  Acetylcholinesterase Blood Cells Brain Matter Cell Signaling Cellular Reactions Central Nervous System Disorders Chlorpyrifos Corticosteroids Cytokines Dichlorvos Enzyme Inhibitors Exposure Assessment Exposure Levels Gene Regulation Immune Reaction Laboratory Animals Laboratory Testing Military Personnel Neurological Disorders Neurological Reactions Neuromuscular System Neurotoxic Agents Neurotoxic Disorders Neurotransmitters Organophosphorus Compounds Organophosphorus Pesticides Phosphates Physiological Stress Proteins Ribonucleic Acids RNA Sarin

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; 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:
  174
• Issue:
  1
• NIOSHTIC Number:
  nn:20058997
• Citation:
  Toxicologist 2020 Mar; 174(1):489
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2) ; Dichlorvos (CAS RN 62-73-7) ; Diisopropyl fluorophosphate (CAS RN 55-91-4) ; Pyridostigmine (CAS RN 155-97-5) ; Sarin (CAS RN 107-44-8)
• Federal Fiscal Year:
  2020
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 59th Annual Meeting and ToxExpo, March 15-19, 2020, Anaheim, California
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:e40a64e081fe9d2f4c63163864082621f14296dcf884874e8a6ee4c92821af9c41c2410c17ad7c8b83a32b0c62016c09b51fae56eebf2e97e860b442233332a9
• Download URL:
  https://stacks.cdc.gov/view/cdc/223336/cdc_223336_DS1.pdf
• File Type:
  [PDF - 521.86 KB ]