Abstract
Background: Accumulating public health and epidemiological literature support the hypothesis that arsenic in drinking water or food affects the brain adversely. Methods: Experiments on the consequences of nitric oxide (NO) formation in neuronal cell culture and mouse brain were conducted to probe the mechanistic pathways of nitrosative damage following arsenic exposure. Results: After exposure of mouse embryonic neuronal cells to low doses of sodium arsenite (SA), we found that Ca2+ was released leading to the formation of large amounts of NO and apoptosis. Inhibition of NO synthase prevented neuronal apoptosis. Further, SA led to concerted S-nitrosylation of proteins significantly associated with synaptic vesicle recycling and acetyl-CoA homeostasis. Our findings show that low-dose chronic exposure (0.1–1 ppm) to SA in the drinking water of mice led to S-nitrosylation of proteomic cysteines. Subsequent removal of arsenic from the drinking water reversed the biochemical alterations. Conclusions: This work develops a mechanistic understanding of the role of NO in arsenic-mediated toxicity in the brain, incorporating Ca2+ release and S-nitrosylation as important modifiers of neuronal protein function.
Highlights
Living in areas contaminated with arsenic can affect the cognitive development of children
The results suggest the involvement of calcium, nitric oxide (NO), and apoptosis in the mechanism of cognitive behavior alteration in arsenic-treated mice
Since Ca2+/calmodulin is one of the main regulators of nNOS activity [23], we first tested whether Ca2+ is released from cellular stores following arsenic exposure [28], leading to NO generation and the resultant S-nitrosylation and nitration of proteins [23]
Summary
Living in areas contaminated with arsenic can affect the cognitive development of children. The scientists found that children with an arsenic level in urine exceeding 50 μg/L had significantly weaker cognitive abilities than those with a urine arsenic concentration of below 50 μg/L [1] Another large-scale observational study has shown that autistic spectrum disorder prevailed in census tracts located in the areas polluted with arsenic, lead, and mercury [2]. An association was found between lower IQ in children and exposure to arsenic in drinking water [3]. Experiments on rats exposed to arsenic at the concentration of 68 mg/L in drinking water have demonstrated spatial memory damage due to morphological and biochemical abnormalities in hippocampus [9]. Similar results have been shown in the epidemiological studies on children and adults consuming water with low concentrations of arsenic. Conclusions: This work develops a mechanistic understanding of the role of NO in arsenic-mediated toxicity in the brain, incorporating Ca2+ release and S-nitrosylation as important modifiers of neuronal protein function
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