Impact of gulf war toxic exposures after mild traumatic brain injury

Abstract

Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery.

Cognitive and Cellular Effects of Combined Organophosphate Toxicity and Mild Traumatic Brain Injury

“…The hypothesis that emerged from early studies was that GWI might be a disorder that is also expressed neuropathologically. More recently, animal studies have indicated that the effects of toxicant exposure in combination with TBI can lead to more severe consequences in the brain [36]. Both our behavioral and immunohistochemistry results support the additive effect of the combined insults.…”

Military exposures and Gulf War illness in veterans with and without posttraumatic stress disorder

“…The finding from a previous study that severe GWI was more frequent in veterans who were GWI+/PTSD+ compared to veterans who were GWI+/PTSD-is consistent with this line of thinking (Malhotra et al, 2023). This account of GWI is similar to a recent theory of GWI that posits that the condition, especially its more severe manifestation, is the result of "multiple hits" of neurotoxicant exposures and traumatic brain injury (Ferguson et al, 2022) and the reason many murine models of GWI combine stress and neurotoxicant exposures to recapitulate GWI (Ashbrook et al, 2018;Macht et al, 2019;Michalovicz et al, 2020).…”

Long Noncoding RNA VLDLR-AS1 Levels in Serum Correlate with Combat-Related Chronic Mild Traumatic Brain Injury and Depression Symptoms in US Veterans

“…Hence, our measurements in patient samples are highly relevant, as the findings can be directly translated to clinical settings. Individuals who have endured mTBI, and particularly those with rmTBI, often have concomitant long-term neurological symptoms, including a decline in cognition, motor abilities and changes in behavior [81][82][83][84][85]. Extensive neuropsychological testing procedures have been established to evaluate the long-term effects, which include clinical assessments, as well as self-administered questionnaires, such as NSI-22 and PHQ-9 [86][87][88].…”