Exposure to an organophosphate pesticide, individually or in combination with other Gulf War agents, impairs synaptic integrity and neuronal differentiation, and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure

Abstract

Gulf War illness (GWI) is a currently untreatable multi-symptom disorder experienced by 1990-1991 Persian Gulf War (GW) veterans. The characteristic hallmarks of GWI include cognitive dysfunction, tremors, migraine, and psychological disturbances such as depression and anxiety. Meta-analyses of epidemiological studies have consistently linked these symptomatic profiles to the combined exposure of GW agents such as organophosphate-based and pyrethroid-based pesticides (e.g. chlorpyrifos (CPF) and permethrin (PER) respectively) and the prophylactic use of pyridostigmine bromide (PB) as a treatment against neurotoxins. Due to the multi-symptomatic presentation of this illness and the lack of available autopsy tissue from GWI patients, very little is currently known about the distinct early pathological profile implicated in GWI (including its influence on synaptic function and aspects of neurogenesis). In this study, we used preclinical models of GW agent exposure to investigate whether 6-month-old mice exposed to CPF alone, or a combined dose of CPF, PB and PER daily for 10 days, demonstrate any notable pathological changes in hippocampal, cortical (motor, piriform) or amygdalar morphometry. We report that at an acute post-exposure time point (after 3 days), both exposures resulted in the impairment of synaptic integrity (reducing synaptophysin levels) in the CA3 hippocampal region and altered neuronal differentiation in the dentate gyrus (DG), demonstrated by a significant reduction in doublecortin positive cells. Both exposures also significantly increased astrocytic GFAP immunoreactivity in the piriform cortex, motor cortex and the basolateral amygdala and this was accompanied by an increase in (basal) brain acetylcholine (ACh) levels. There was no evidence of microglial activation or structural deterioration of principal neurons in these regions following exposure to CPF alone or in combination with PB and PER. Evidence of subtle microvascular injury was demonstrated by the reduction of platelet endothelial cell adhesion molecule (PECAM)-1 levels in CPF+PB+PER exposed group compared to control. These data support early (subtle) neurotoxic effects on the brain following exposure to GW agents.

Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation

“…The role pf PB in in causing neuroinflammation is unclear. Though GW-chemical exposure that included PB caused astrocytic activation and ICAM-1 increase a firm mechanistic argument in favor of the neuroinflammatory pathology is lacking[7]. [10, 68].…”

“…Mice were exposed to gulf war chemicals based on established rodent models of Gulf War Illness with some modifications[7, 10]. The treated mice group (GW-T) and TLR4 KO (GW-TLR4 KO) mice group were dosed tri-weekly for one week with PB (2mg/kg) and Permethrin.…”

Trends in brain cancer mortality among U.S. Gulf War veterans: 21 year follow-up

“…There are concerns about the potential health effects of the many environmental exposures during the Gulf War, including oil well fire smoke, nerve agents (sarin and cyclosarin), multiple vaccinations, pyridostigmine bromide, pesticides, and depleted uranium [7,9,10,13-15]. Both human (Gulf War veteran populations) and animal studies have reported neurological outcomes associated with the exposures present during Gulf War deployment, including neuro-inflammation [16], changes in brain volume [17], hippocampal dysfunction [18,19], decreased white matter [7,9,20] and alterations in executive function and cognition [21,22].…”

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

“…Toxins such as lead, methylmercury, organophosphates, and arsenic have been associated with psychiatric disorders, including depression, in a number of epidemiological studies (Zierold et al, 2004; Sen and Sarathi Biswas, 2012; Beard et al, 2013; Freire and Koifman, 2013; Malekirad et al, 2013; Ojo et al, 2014; Weisskopf et al, 2013). Yet, the impact of environmental factors, particularly toxins, on the susceptibility to depression has not been investigated in great detail.…”