Low-Dose Sarin Exposure Produces Long Term Changes in Brain Neurochemistry of Mice

Abstract

Sarin is a toxic organophosphorus (OP) nerve agent that has been reported to cause long-term alterations in behavioral and neuropsychological processes. The present study was designed to investigate the effect of low dose sarin exposure on the monoamine neurotransmitter systems in various brain regions of mice. The rationale was to expand our knowledge about the noncholinergic neurochemical alterations associated with low dose exposure to this cholinesterase inhibitor. We analyzed the levels of monoamines and their metabolites in different brain areas after exposure of male C57BL/6 mice to a subclinical dose of sarin (0.4 LD50). Mice did not show any signs of cholinergic toxicity or pathological changes in brain tissue. At 1, 4 and 8 weeks post-sarin exposure brains were collected for neurochemical analysis. A significant decrease in the dopamine (DA) turnover, as measured by the metabolite to parent ratio, was observed in the frontal cerebral cortex (FC) at all time points tested. DA turnover was significantly increased in the amygdala at 4 weeks but not at 1 or 8 weeks after exposure. The caudate nucleus displayed a decrease in DA turnover at 1 week but no significant change was observed at 4 and 8 weeks suggesting a reversible effect. In addition to this, serotonin (5-HT) levels were transiently altered at various time points in all the brain regions studied (increase in FC, caudate nucleus and decrease in amygdala). Since there were no signs of cholinergic toxicity or cell death after sarin exposure, different non-cholinergic mechanisms may be involved in regulating these effects. Our results demonstrate that non-symptomatic dose of OP nerve agent sarin has potent long-term, region-specific effects on the monoaminergic neurotransmitter systems. Data also suggests differential effects of sarin on the various DA projections. These neurochemical alterations could be associated with long term behavioral and neuropsychological changes associated with low dose OP exposure.

Low-level repeated exposure to diazinon and chlorpyrifos decrease anxiety-like behaviour in adult male rats as assessed by marble burying behaviour

“…There is evidence that OP-induced effects on the 5-HT system components progress with time, albeit at much higher exposure levels (el-Etri, Nickell et al 1992;Pung, Klein et al 2006;Moreno, Canadas et al 2008;Oswal, Garrett et al 2013). Consistent with this, we observed that 5-HT turnover was elevated 6 days after cessation of exposure in comparison to 1 day with a trend towards significance.…”

Succumbing to the laws of attraction

“…These exposures include the stresspotentiated effects of DEET (N, N-Diethyl-meta-toluamide), 5 pyridostigmine bromide (PB), 6,7 and sarin. 8,9 Although the specific triggers continue to be investigated, studies involving molecular and cellular profiling in human subjects strongly support persistent immune dysfunction as a component of this complex disorder. Ongoing T-helper type 1 (Th1) immune activation, as measured by intracellular production of cytokines in peripheral blood, appears to be symptomatic in afflicted Gulf War veterans when compared with healthy counterparts.…”

The sarin-like organophosphorus agent bis(isopropyl methyl)phosphonate induces ER stress in human astrocytoma cells

“…However, recent studies indicated that OP compounds could induce nerve disorders without inhibiting AChE (Terry, 2012). The mechanisms underlying the toxicity of OP compounds are of great interest to toxicologists as their clarifi cation could lead to treatments for the delayed neurotoxicity caused by OP agents (Banks and Lein, 2012;Lee et al, 2014;Oswal et al, 2013). Several studies showed that OP agents impair various cell organelles such as mitochondria (KaramiMohajeri and Abdollahi, 2013), DNA (Mostafalou and Abdollahi, 2013), and the cytoskeleton (Grigoryan et al, 2008).…”