Abstract
Gulf War Illness (GWI) is a chronic multi-symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War; the constellation of “sickness behavior” symptoms observed in ill veterans is suggestive of a neuroimmune involvement. Various chemical exposures and conditions in theater have been implicated in the etiology of the illness. Previously, we found that GW-related organophosphates (OPs), such as the sarin surrogate, DFP, and chlorpyrifos, cause neuroinflammation. The combination of these exposures with exogenous corticosterone (CORT), mimicking high physiological stress, exacerbates the observed neuroinflammation. The potential relationship between the effects of OPs and CORT on the brain versus inflammation in the periphery has not been explored. Here, using our established GWI mouse model, we investigated the effects of CORT and DFP exposure, with or without a chronic application of pyridostigmine bromide (PB) and N,N-diethyl-meta-toluamide (DEET), on cytokines in the liver and serum. While CORT primed DFP-induced neuroinflammation, this effect was largely absent in the periphery. Moreover, the changes found in the peripheral tissues do not correlate with the previously reported neuroinflammation. These results not only support GWI as a neuroimmune disorder, but also highlight the separation between central and peripheral effects of these exposures.
Highlights
One-third of the veterans of the 1991 Persian Gulf War returned from duty with a chronic multi-symptom disorder, termed Gulf War Illness (GWI), experiencing fatigue, chronic pain, cognitive dysfunction, and headaches among many other symptoms (Fukuda et al, 1998; Steele, 2000; Smith et al, 2013; Dursa et al, 2016; White et al, 2016)
We have demonstrated that exposure to the organophosphate (OP), irreversible acetylcholinesterase (AChE) inhibitors diisopropyl fluorophosphate (DFP), as a sarin surrogate, and the pesticide chlorpyrifos results in neuroinflammation in rodents that is further exacerbated by prior chronic exposure to the stress hormone corticosterone at levels associated with high physiological stress (O’Callaghan, et al, 2015; Locker et al, 2017; Koo et al, 2018; Miller et al, 2018)
Considering that pyridostigmine bromide (PB) was used as a prophylactic against nerve agents to counteract the lethal peripheral symptoms of cholinergic toxicity (i.e. SLUDGEM) (Keeler et al, 1991; Research Advisory Committee (RAC) (2008)) and that many of the chemical exposures experienced during the war would have resulted in a whole-body exposure, we wished to investigate the peripheral consequences of exposure in our GWI mouse model by examining inflammatory cytokines in the liver (Fig. 1) and serum (Figs. 2 and 3) of exposed mice
Summary
One-third of the veterans of the 1991 Persian Gulf War returned from duty with a chronic multi-symptom disorder, termed Gulf War Illness (GWI), experiencing fatigue, chronic pain, cognitive dysfunction, and headaches among many other symptoms (Fukuda et al, 1998; Steele, 2000; Smith et al, 2013; Dursa et al, 2016; White et al, 2016). While epidemiological studies have focused significant attention on the potential for the nerve agent prophylactic and reversible AChE inhibitor pyridostigmine bromide (PB) to contribute to GWI (Sullivan et al, 2003; Steele et al, 2012; Sullivan et al, 2018), our prior work found no neuroinflammatory effects of acute PB exposure (Locker et al, 2017; Miller et al, 2018) or chronic PB exposure combined with the insect repellant N,N-diethyl-meta-toluamide (DEET)(O’Callaghan et al, 2015). In order to evaluate the potential systemic or peripheral inflammatory effects of GW-relevant toxicant exposures, we evaluated the expression of inflammatory cytokines in the liver and serum of mice we have previously reported to have a neuroinflammatory response to our model of GWI (O’Callaghan et al, 2015)
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