Multi-Omic Analysis Reveals Brain-Blood Concordance and Persistent Neuroimmune Reprogramming with Stress and Toxicant Exposure in a Mouse Model of Gulf War Illness

Details

• Journal Article:
  Brain, Behavior, & Immunity - Health
• Personal Author:
  Sasaki, A. ; Kelly, K. A. ; Michalovicz, Lindsay T. ; Ashbrook, D. G. ; Wijenayake, S. ; O'Callaghan, James P. ; McGowan, P. O.
• Description:
  Gulf War Illness (GWI) is a chronic neuroimmune condition affecting veterans of the 1990-91 Gulf War. Current treatments primarily target symptom relief, and the biological mechanisms underlying GWI remain poorly understood. Using a validated mouse model of Gulf War Illness (GWI) combining corticosterone (CORT) and diisopropyl fluorophosphate (DFP) exposure to induce stress- and toxicant-related neuroimmune priming, we examined how prior exposure alters molecular responses to a subsequent immune challenge. Male mice were exposed to CORT and DFP with repeated intermittent CORT, followed by lipopolysaccharide (LPS) or saline to assess transcriptional and epigenetic changes in brain and blood. We analysed transcript abundance, chromatin accessibility, and DNA methylation in the hippocampus, frontal cortex, and blood at 6 h, 12 h and 24hrs after LPS challenge (3-4 mice per group). We identified widespread transcriptional changes and dynamic chromatin accessibility following LPS exposure, with DNA methylation modifications that persisted in the hippocampus and blood. Thirty-three genes, including Stat3, Plpp3, Cdkn1a, and Fgfr2, were differentially expressed and methylated in both hippocampus and blood across all time points. These genes clustered in immune- and glial-related pathways. Transcription factor analysis revealed enrichment of NF-kB, CREB1, EGR1, JUN, and MYC binding motifs in regions with differential methylation. Our findings identify novel candidate biomarkers in peripheral blood that reflect brain molecular changes, providing a new framework for elucidating the long-term epigenetic impacts of stress and toxicant exposure in GWI.
• Subjects:
  Biomarkers DNA Damage Inflammation Occupational Health Persian Gulf Syndrome Safety
• Keywords:
  Author Keywords: Gulf War Illness; Neuroinflammation; DNA Methylation Modifications; Hippocampus; Stress And Toxicant Exposure; Transcriptomics; Epigenetic Signatures Military Personnel; Neurological Disorders; Chronic Inflammation; Immune Reaction; DNA Damage; Stress; Molecular Biology; Biomarkers; Genomics;
• Source:
  Brain Behav Immun Health 2026 May; 53:101207
• ISSN:
  2666-3546
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  West Virginia ; Tennessee ; Philadelphia Region [OSHA] ; Birmingham Region [OSHA]
• 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:
  12 pdf pages
• Volume:
  53
• NIOSHTIC Number:
  nn:20071460
• Contact Point Address:
  P.O. McGowan, Department of Biological Sciences, University of Toronto, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada
• Email:
  patrick.mcgowan@utoronto.ca
• Federal Fiscal Year:
  2026
• Peer Reviewed:
  True
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:5df5497a382f09947bc0d55354c9796f49d336ab19951f7b6293b0f562695eb3b3bdadeec0e45db7ffc7dfa23f362685e8c23c9482a31d555df83c7d073a981b
• Download URL:
  https://stacks.cdc.gov/view/cdc/259058/cdc_259058_DS1.pdf
• File Type:
  [PDF - 3.42 MB ]