Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ijms21113948
Keywords
Arsenic; nitric oxide; S-nitrosylation; brain disorders; brain cortex; mouse; nitrosative stress; apoptosis; synaptic processes; acetyl-CoA
Funding
- MIT Center for Environmental Health Sciences [ES002109]
- Simons Foundation
- NIH/NCI [CA26731]
- Army Institute for Collaborative Biotechnologies [W911NF-19-2-0026]
- 2016 MINT Funds-MIT McGovern Institute for Brain Research
- Satell Family Foundation
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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.
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