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.

Citation:

Haitham Amal, Guanyu Gong, Hongmei Yang, Brian A Joughin, Xin Wang, Charles G Knutson, Maryam Kartawy, Igor Khaliulin, John S Wishnok, and Steven R Tannenbaum. 2020. “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.” International journal of molecular sciences, 21, 11.

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 Ca(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(2+) release and S-nitrosylation as important modifiers of neuronal protein function.