Low Doses of Arsenic in a Mouse Model of Human Exposure and in Neuronal Culture Lead to S-Nitrosylation of Synaptic Proteins and Apoptosis via Nitric Oxide

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 th...

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Bibliographic Details
Main Authors: Amal, Haitham, Gong, Guanyu, Yang, Hongmei, Joughin, Brian A., Wang, Xin, Knutson, Charles G. F., Kartawy, Maryam, Khaliulin, Igor, Wishnok, John S., Tannenbaum, Steven R
Other Authors: Massachusetts Institute of Technology. Department of Biological Engineering
Format: Article
Published: Multidisciplinary Digital Publishing Institute 2020
Online Access:https://hdl.handle.net/1721.1/126759
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Summary: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 Ca[superscript 2+] 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 Ca[superscript 2+] release and S-nitrosylation as important modifiers of neuronal protein function.