Abstract
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-κB, 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.