Multi-omic analysis reveals brain-blood concordance and persistent neuroimmune reprogramming with stress and toxicant exposure in a mouse model of Gulf War Illness [RRBS]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE325694 | GEO | 2026/03/27
REPOSITORIES: GEO
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Project description:Gulf War Illness (GWI) is a chronic multisymptom disorder associated with prior stress and toxicant exposures. Adult male C57BL/6J mice were exposed to corticosterone (CORT) and diisopropyl fluorophosphate (DFP), followed by repeated intermittent CORT and a later immune challenge with lipopolysaccharide (LPS) or saline. RNA-seq was performed in hippocampus and frontal cortex collected 6 h, 12 h, and 24 h after challenge to define transcriptional responses associated with persistent neuroimmune priming in this mouse model of GWI.
2026-03-27 | GSE325692 | GEO
Project description:Gulf War Illness (GWI) is a chronic multisymptom disorder associated with prior stress and toxicant exposures. Adult male C57BL/6J mice were exposed to corticosterone (CORT) and diisopropyl fluorophosphate (DFP), followed by repeated intermittent CORT and a later immune challenge with lipopolysaccharide (LPS) or saline. ATAC-seq was performed in hippocampus and frontal cortex to assess chromatin accessibility responses associated with persistent neuroimmune priming.
2026-03-27 | GSE325684 | GEO
Project description:Of the nearly 1 million military personnel who participated in the 1990-1991 Gulf War, between 25% and 35% became ill with what now is referred to as Gulf War Illness (GWI), by the Department of Defense. Symptoms varied from gastrointestinal distress to lethargy, memory loss, inability to concentrate, depression, respiratory and reproductive problems. The symptoms have persisted for 30 years in those afflicted but the basis of the illness remains largely unknown. Nerve agents and other chemical exposures in theater have been implicated but the long-term effects of these acute exposures have left few if any identifiable signatures. The major aim of this study is to elucidate the possible genomic basis for the persistence, especially of the neurological and behavioral effects. To address this, we performed a whole genome epigenetic analysis of the proposed cause of GWI, viz., exposure to organophosphate neurotoxicants combined with high circulating glucocorticoids in two inbred mouse strains, C57BL/6J and DBA/2J. The animals received corticosterone in their drinking water (20mg%, w/v) for 7 days followed by injection of diisopropylfluorophosphate, a nerve agent surrogate (DFP, 4mg/kg, i.p.). Control mice were maintained under normal husbandry. Six weeks after DFP injection, the animals were euthanized and medial prefrontal cortex harvested for genomic methylation analysis by MBD-seq. We observed 67 differentially methylated genes, notably among them, Ttll7, Akr1c14, Slc44a4, and Rusc2, all related to different symptoms of GWI. Our results support proof of principle of genetic differences in the chronic effects of GWI-related exposures and may reveal why the disease has persisted in many of the now aging Gulf War veterans.
2023-06-01 | GSE225179 | GEO
Project description:This pilot study enrolled 9 GWI (Gulf War Illness) cases identified from the Department of Veterans Affairs GWI registry, and 11 sedentary control veterans who had not been deployed to the Persian Gulf and were matched to cases by sex, body mass index (BMI) and age.<br>We exposed GWI patients and matched controls to an exercise challenge to explore differences in immune cell function measured by classic immune assays and gene expression profiling.
2009-02-24 | E-MEXP-2069 | biostudies-arrayexpress
Project description:Aims: In an effort to gain further insight into the underlying mechanisms tied to disease onset and progression of Gulf War Illness (GWI), our team evaluated GWI patient response to stress utilizing RNA-Seq. Main Methods: The protocol included blood collection before (baseline), during (peak of exercise, measured by VO2 max), and after exercise challenge (recovery – four hours post-exercise challenge). Peripheral blood mononuclear cell (PBMC) transcriptomics data were analyzed using DESeq2 and DEXseq software to understand why GWI patients process stressors differently from their healthy counterparts. Key findings: Our findings validate previously identified dysregulation of immune and inflammatory pathways among GWI patients as well as highlight novel immune and inflammatory markers of disease activity. These results provide a foundation for future research efforts in understanding GWI pathophysiology and creating targeted treatments. Significance: Gulf War Illness is a complex, chronic, and debilitating multi-system illness impacting 25%-30% of the U.S. troops deployed to the 1990-1991 Gulf War. The condition is characterized by medically unexplained fatigue and affects multiple organ systems. Because the underlying mechanisms are largely unknown, patients receive symptom-based treatment, rather than targeting fundamental biological processes. To the best of our knowledge, this is the first study that applies RNA-Seq to analyze the effect of GWI, and the response to stressors in GWI, on the transcriptomic changes in circulating immune cells.
2021-08-15 | GSE168409 | GEO
Project description:Background Gulf War Illness (GWI) is a severely debilitating condition with chronic symptoms affecting up to 30% of the veterans deployed to the 1990-91 Persian Gulf War. The symptoms associated with GWI include fatigue, musculoskeletal/joint pain and disturbances of multiple organ systems. The mechanisms of GWI are unknown, although the symptoms suggest that GWI is most likely caused by a combination of genetic predisposition and it’s interaction with environmental factors such as exposure to toxic chemicals. Objectives This research project aims to assess how sex differences in individuals with GWI impact their response to stress, specifically through an exercise challenge. Additionally, it highlights the importance of considering sex differences in the diagnosis and treatment of GWI. Methods We utilized RNA-seq to examine the differential gene expression (GE) in peripheral blood mononuclear cells of 24 female GWI patients, 20 male GWI patients, and 40 healthy controls (HC) who were matched in for sex, age, and BMI. We evaluated the gene expression changes at three time points: T0 (baseline), T1 (at maximal exertion), and T2 (4 hours into recovery after T1). To ensure consistency, we excluded genes located on the sex chromosomes and performed separate analyses for men and women. Our focus was to compare the response to exercise within each group (GWI patients and HC) between different time points. Results In the male GWI cohort, pathways associated with immune system process, particularly IL-12, and natural killer cell cytotoxicity were activated during exercise. The female GWI patients exhibited less significant changes in gene expression than men. During the recovery period, male GWI patients demonstrated distinct alterations in the regulation of innate immune responses. On the other hand, female GWI patients showed significant changes in genes related to regulation of intracellular signal transduction. These functional pathways and differentially expressed genes identified in this project provide valuable insights into the sex-specific pathophysiology of GWI. Conclusion The identification of sex-specific biomarkers and therapeutic targets in GWI holds great potential for understanding the distinct onset and progression of this disease in different sexes.
2025-04-30 | GSE286345 | GEO
Project description:Gulf War Illness (GWI) is a complex condition affecting Veterans, and its underlying neuropathological mechanisms remain unclear. Patient-derived induced pluripotent stem cells (iPSCs) offer a platform to model the disease in vitro. Objective: To map transcriptomic landscapes and infer single-cell gene regulatory networks (scGRNs) in iPSC-derived neurons from symptomatic and non-symptomatic Gulf War Veterans to identify genes and pathways implicated in GWI pathophysiology and predisposition. Design, Setting, and Participants: This study utilized iPSCs generated from symptomatic GWI Veterans and non-symptomatic GWI Veteran controls. Neurons were differentiated from these iPSCs for analysis. Main Outcomes and Measures: Single-cell RNA sequencing (scRNAseq) was used to generate transcriptomic data. Machine learning algorithms were applied to infer and compare scGRNs between the symptomatic and non-symptomatic groups, identifying key regulatory differences. Results: Analysis of scRNAseq data revealed significant differences in gene expression profiles between neurons derived from symptomatic and non-symptomatic Veterans. scGRN inference identified distinct regulatory modules associated with GWI symptom status. Key transcription factors driving these differences were identified, along with target genes involved in neuroinflammatory responses, synaptic signaling, and stress response pathways. These findings point towards specific molecular dysregulations contributing to GWI neuropathology. Conclusions and Relevance: This study demonstrates the utility of iPSC-derived neurons coupled with single-cell transcriptomics and computational network inference for investigating GWI. The identified differences in scGRNs provide novel insights into the molecular underpinnings of the illness and highlight potential targets for future diagnostic and therapeutic strategies.
2026-01-01 | GSE303735 | GEO
Project description:Gulf War Illness (GWI) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as memory and other neurological problems, muscle and joint pain, gastrointestinal issues, hormonal imbalance, immune dysfunction and debilitating fatigue. Currently, treatment of the condition relies solely on management of symptomatology and improvement in quality of life due to a lack of knowledgeof the underlying mechanisms of disease onset and progression. An improved understanding of the key mechanisms of GWI and dysfunction within regulatory systems will lead to more objective diagnosis methods and adequate management of patients by providing targeted approaches to treatment. Disruption of DNA methylation patterns has been tied to various immune, neurological and endocrine disease states; however, the status of this epigenetic mark in GWI remains uncertain. This study aimed at identifying biomarkers of GWI by gaining knowledge on DNA methylation patterns of GWI in an effort to determine therapeutic targets of disease activity and provide insight into disease onset and progression. Methods: Genomic DNA from 10 GWI patients and 10 healthy controls [HC] (“experimental cohort”) prepared from PBMCs was analyzed with ELISA-based DNA methylation assays and Illumina MethylationEPIC microarrays. These arrays allow measuring the methylation status at 850,000 CpG sites. Methylation changes in promoter regions were separately analyzed and used as input data in ingenuity pathway analysis software to identify altered functional pathways. Relevant differentially methylated CpG sites (DMS) were validated by pyrosequencing. Results: Global DNA methylation levels using the ELISA-based assay on the DNA isolated from PBMCs of GWI patients were similar to those of HC. However, deeper evaluation using microarray-based genome-wide technology allowed detection of DMS in GWI patients with respect to HC. As an overall 10,767 CpG sites presented with differential DNA methylation levels across promoters, gene regulatory elements and within coding regions of genes. Majority of these DMS were hypermethylated in GWI patients as compared to the HC, and more than half of these sites localized to promoters and gene regulatory elements, relative to distribution of DMSin the network as a whole, indicating gene regulatory potential. Functional pathway analysis of the 776 genes with differentially methylated promoters (DMPs) fulfilling FDR≤0.2 criteriafollowing a genomic region-based approachlinks GWI to defects in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with GWI using the new MethylationEPIC microarrays covering about 850,000 CpG sites; which builds on previous methylation preliminary reports. The data obtained are consistent with previous evidence for dysregulation of the immune system in GWI and suggests a role of this epigenetic modification on the DNA pathobiology of GWI. They are also consistent with previous reports showing a Th1- to Th2-mediated immune response shift in GWI in addition to altered immune system function. Future validation studies in larger cohorts of GWI patients and evaluation of the effects of these methylation patterns on gene expression regulation are granted.
2019-03-15 | GSE112905 | GEO
Project description:Gulf War Illness (GWI) is a diverse set of neurologic and systemic symptoms affecting many veterans deployed in the Persian Gulf War, but its etiology is unknown and treatment options are limited. Veterans with GWI were exposed to a variety of agents, including pyridostigmine bromide, used as prophylaxis against nerve agents, intranasal lipopolysaccharide (LPS) from desert sandstorms, and chronic unpredictable stress (CUS) from combat. Here, we investigated the gene expression effects of these three Gulf War-related exposures (GWE) in adult rat frontal cortex (FC) and lateral amygdala (LA) using Clariom S microarrays. We found 138 transcript clusters (TCs) in LA and 38 TCs in FC differentially expressed between the group with GWE (n=2) compared to naïve controls (n=3, FDR <10%). These TCs included genes involved in inflammation such as Fosb (pmin=1.02e-5) and Junb (pmin=1.13e-5). Gene ontology analysis found enrichment of differentially expressed genes in “T cell differentiation” (pmin=8.71e-5) and “response to organophosphorus” (pmin=1.74e-8), among other categories. Lastly, we found that prophylactic treatment with rosiglitazone, a PPAR- agonist, reduced gene expression changes associated with GWE (in LA: 115/138 [83.3%] TCs with reduced changes, χ2=61.33, p=4.82e-15). These results suggest our rat model of GWI is associated with gene expression changes related to neuroinflammation and that some of these molecular changes may be mitigated by rosiglitazone prophylaxis.
2021-06-01 | GSE165221 | GEO
Project description:Differentially expressed genes may provide insight into the underlying mechanisms of Gulf War Illness involved in neurodegeneration.
2021-07-27 | GSE180786 | GEO