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Open AccessArticle

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

1
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
2
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
4
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(11), 3948; https://doi.org/10.3390/ijms21113948
Received: 12 May 2020 / Revised: 26 May 2020 / Accepted: 27 May 2020 / Published: 31 May 2020
(This article belongs to the Special Issue Cellular Secretomes)
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. View Full-Text
Keywords: Arsenic; nitric oxide; S-nitrosylation; brain disorders; brain cortex; mouse; nitrosative stress; apoptosis; synaptic processes; acetyl-CoA Arsenic; nitric oxide; S-nitrosylation; brain disorders; brain cortex; mouse; nitrosative stress; apoptosis; synaptic processes; acetyl-CoA
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Amal, H.; Gong, G.; Yang, H.; Joughin, B.A.; Wang, X.; Knutson, C.G.; Kartawy, M.; Khaliulin, I.; Wishnok, J.S.; Tannenbaum, S.R. 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. Int. J. Mol. Sci. 2020, 21, 3948.

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