Exposure to Gulf War Illness-related agents leads to the development of chronic pain and fatigue

Nguyen, Huy; Sahbaie, Peyman; Goba, Lihle; Sul, Julian; Suzaki, Aoi; Clark, J. David; Huang, Ting‐Ting

doi:10.1016/j.lfs.2021.119867

Cited by 8 publications

(5 citation statements)

References 54 publications

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“…In fact, consistent with evidence suggesting that pesticides beyond organophosphates (including pyrethroids, organochlorines) may be implicated in GWI 48 , multiple pesticide classes share metabolomic signatures consistent with fatty acid oxidation involvement 57 . Gulf War illness animal model muscle biopsy data show a reduction in succinate dehydrogenase activity (used as an index of complex II activity) 36 .…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity

Golomb

Baez

Schilling

et al. 2023

Sci Rep

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Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function—but not peripheral inflammation—predicts greater GWI symptoms and severity.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity

Golomb

Baez

Schilling

et al. 2023

Sci Rep

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“…A series of studies in a rat model demonstrated that oral administration of PB, along with a dermal application of low doses of DEET and PER for four weeks with or without mild to moderate stress, results in chronic GWI-like symptoms with multiple pathological changes in the brain have corroborated the chemical exposure hypothesis of GWI (11)(12)(13)(14)(15)(16)(17)(18)(19). Additional animal studies utilizing exposure to sarin surrogate diisopropyl fluorophosphate, chlorpyrifos, or various combinations of GWIrelated chemicals have also validated the chemical exposure hypothesis of GWI (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 89%

Brain-Specific Increase in Leukotriene Signaling Accompanies Chronic Neuroinflammation and Cognitive Impairment in a Model of Gulf War Illness

Attaluri

Upadhya²,

Kodali³

et al. 2022

Front. Immunol.

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Persistent cognitive impairment is a primary central nervous system-related symptom in veterans afflicted with chronic Gulf War Illness (GWI). Previous studies in a rat model have revealed that cognitive dysfunction in chronic GWI is associated with neuroinflammation, typified by astrocyte hypertrophy, activated microglia, and enhanced proinflammatory cytokine levels. Studies in a mouse model of GWI have also shown upregulation of several phospholipids that serve as reservoirs of arachidonic acid, a precursor of leukotrienes (LTs). However, it is unknown whether altered LT signaling is a component of chronic neuroinflammatory conditions in GWI. Therefore, this study investigated changes in LT signaling in the brain of rats displaying significant cognitive impairments six months after exposure to GWI-related chemicals and moderate stress. The concentration of cysteinyl LTs (CysLTs), LTB4, and 5-Lipoxygenase (5-LOX), the synthesizing enzyme of LTs, were evaluated. CysLT and LTB4 concentrations were elevated in the hippocampus and the cerebral cortex, along with enhanced 5-LOX expression in neurons and microglia. Such changes were also associated with increased proinflammatory cytokine levels in the hippocampus and the cerebral cortex. Enhanced CysLT and LTB4 levels in the brain could also be gleaned from their concentrations in brain-derived extracellular vesicles in the circulating blood. The circulating blood in GWI rats displayed elevated proinflammatory cytokines with no alterations in CysLT and LTB4 concentrations. The results provide new evidence that a brain-specific increase in LT signaling is another adverse alteration that potentially contributes to the maintenance of chronic neuroinflammation in GWI. Therefore, drugs capable of modulating LT signaling may reduce neuroinflammation and improve cognitive function in GWI. Additional findings demonstrate that altered LT levels in the brain could be tracked efficiently by analyzing brain-derived EVs in the circulating blood.

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“…The consequences of GWI-related chemical exposure in mice have been well documented across multiple studies in the last few decades (Kodali et al, 2018;Nguyen et al, 2021). Neuropathologic, immunohistochemical, behavioral, and cognitive deficits are commonly seen when using the GWI mouse model.…”

Section: Monitoring Of Gulf War Illness Signs and Neuropathology Anal...mentioning

confidence: 99%

“…sensitivity tests are also viable options, measuring the latency of the hind paw withdrawal from a radiating temperature stimulus as described previously (Nguyen et al, 2021).…”

Section: Reddy Et Almentioning

confidence: 99%

“…GWI mouse models previously have been tested with multiple nociception threshold protocols. The Von Frey filament test measures mechanical sensitivity through the application of fibers of increasing stiffness to the plantar aspect of the hind paw (Nguyen et al, 2021;Nizamutdinov, Mukherjee, Deng, Stauss, & Shapiro, 2018). Heat and cold…”

Section: Evaluation Of Pain Sensitivitymentioning

confidence: 99%

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Experimental Models of Gulf War Illness, a Chronic Neuropsychiatric Disorder in Veterans

Reddy

Singh

et al. 2023

Current Protocols

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Gulf War illness (GWI) is a chronic multifaceted condition with debilitating pain and fatigue, as well as sleep, behavioral, and cognitive impairments in war veterans. Currently, there is no effective treatment or cure for GWI; therefore, there is a critical need to develop experimental models to help better understand its mechanisms and interventions related to GWI-associated neuropsychiatric disorders. Chemical neurotoxicity appears to be one cause of GWI, and its symptoms manifest as disruptions in neuronal function. However, the mechanisms underlying such incapacitating neurologic and psychiatric symptoms are poorly understood. The etiology of GWI is complex, and many factors including chemical exposure, psychological trauma, and environmental stressors have been associated with its development. Attempts have been made to create GWI-like symptomatic models, including through chronic induction in mice and rats. Here, we present a brief protocol of GWI in rats and mice, which exhibit robust neuropsychiatric signs and neuropathologic changes reminiscent of GWI. This article provides a guide to working protocols, application of therapeutic drugs, outcomes, troubleshooting, and data analysis. Our broad profiling of GWI-like symptoms in rodents reveals features of progressive morphologic and long-lasting neuropsychiatric features. Together, the GWI model in rodents shows striking consistency in recapitulating major hallmark features of GWI in veterans. These models help identify mechanisms and interventions for GWI.

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Exposure to Gulf War Illness-related agents leads to the development of chronic pain and fatigue

Cited by 8 publications

References 54 publications

Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity

Mitochondrial impairment but not peripheral inflammation predicts greater Gulf War illness severity

Brain-Specific Increase in Leukotriene Signaling Accompanies Chronic Neuroinflammation and Cognitive Impairment in a Model of Gulf War Illness

Experimental Models of Gulf War Illness, a Chronic Neuropsychiatric Disorder in Veterans

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