Epigenetic Impacts of Stress Priming of the Neuroinflammatory Response to Sarin Surrogate in Mice: A Model of Gulf War Illness

Details

• Personal Author:
  Ashbrook DG ; Broderick G ; de Vega WC ; Hing B ; Kelly KA ; McGowan PO ; Michalovicz LT ; Miller DB ; Miller JV ; O'Callaghan JP
• Description:
  Background: Gulf War illness (GWI) is an archetypal, medically unexplained, chronic condition characterised by persistent sickness behaviour and neuroimmune and neuroinflammatory components. An estimated 25-32% of the over 900,000 veterans of the 1991 Gulf War fulfil the requirements of a GWI diagnosis. It has been hypothesised that the high physical and psychological stress of combat may have increased vulnerability to irreversible acetylcholinesterase (AChE) inhibitors leading to a priming of the neuroimmune system. A number of studies have linked high levels of psychophysiological stress and toxicant exposures to epigenetic modifications that regulate gene expression. Recent research in a mouse model of GWI has shown that pre-exposure with the stress hormone corticosterone (CORT) causes an increase in expression of specific chemokines and cytokines in response to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. Methods: C57BL/6J mice were exposed to CORT for 4 days, and exposed to DFP on day 5, before sacrifice 6 h later. The transcriptome was examined using RNA-seq, and the epigenome was examined using reduced representation bisulfite sequencing and H3K27ac ChIP-seq. Results: We show transcriptional, histone modification (H3K27ac) and DNA methylation changes in genes related to the immune and neuronal system, potentially relevant to neuroinflammatory and cognitive symptoms of GWI. Further evidence suggests altered proportions of myelinating oligodendrocytes in the frontal cortex, perhaps connected to white matter deficits seen in GWI sufferers. Conclusions: Our findings may reflect the early changes which occurred in GWI veterans, and we observe alterations in several pathways altered in GWI sufferers. These close links to changes seen in veterans with GWI indicates that this model reflects the environmental exposures related to GWI and may provide a model for biomarker development and testing future treatments. [Description provided by NIOSH]
• Subjects:
  Biomarkers Laboratories Nervous System Occupational Health Safety
• Keywords:
  Acetylcholinesterase Acetylcholinesterase Inhibitors AChE Author Keywords: Gulf War Illness Cognitive Function CORT Corticosterone DFP Diisopropyl Fluorophosphate Epigenetics Laboratory Animals Military Personnel Physical Stress Psychological Stress Psychophysiology Sarin Transcriptomics

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• ISSN:
  1742-2094
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Iowa ; OSHA Region 4 ; OSHA Region 7 ; Tennessee
• 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:
  86
• Volume:
  15
• Issue:
  1
• NIOSHTIC Number:
  nn:20051237
• Citation:
  J Neuroinflammation 2018 Mar; 15(1):86
• Contact Point Address:
  Patrick O. McGowan, Department of Biological Sciences and Center for Environmental Epigenetics and Development and Department of Cell and Systems Biology, University of Toronto, Scarborough campus, Toronto, ON, Canada
• Email:
  patrick.mcgowan@utoronto.ca
• CAS Registry Number:
  Diisopropyl fluorophosphate (CAS RN 55-91-4)
• Federal Fiscal Year:
  2018
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Neuroinflammation
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:173c61f94ee3e31fc11994516d387d2acc927944b0a2cbca0b760cc0d7d424cc73810400bdac4cb674d88190e0d1674daafcd86f5208a41c29a6dd90f306b331
• Download URL:
  https://stacks.cdc.gov/view/cdc/211307/cdc_211307_DS1.pdf
• File Type:
  [PDF - 1.82 MB ]