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

Haitham Amal*, Guanyu Gong, Hongmei Yang, Brian A. Joughin, Xin Wang, Charles G. Knutson, Maryam Kartawy, Igor Khaliulin, John S. Wishnok, Steven R. Tannenbaum

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageAmerican English
Article number3948
JournalInternational Journal of Molecular Sciences
Volume21
Issue number11
DOIs
StatePublished - 1 Jun 2020

Bibliographical note

Funding Information:
This work was supported by the MIT Center for Environmental Health Sciences Grant ES002109 a grant from the Simons Foundation to the Simons Center for the Social Brain at MIT, NIH/NCI Grant No. CA26731, Army Institute for Collaborative Biotechnologies Grant W911NF-19-2-0026 (B.A.J), 2016 MINT Funds-MIT McGovern Institute for Brain Research, and The Satell Family Foundation (H.A.) Acknowledgments: We thank Dr. George A. Sarkis for his contribution to analysis of the proteomics and Dr. Sarah M. Lewis for SNOTRAP synthesis.

Funding Information:
Funding: This work was supported by the MIT Center for Environmental Health Sciences Grant ES002109 a grant from the Simons Foundation to the Simons Center for the Social Brain at MIT, NIH/NCI Grant No. CA26731, Army Institute for Collaborative Biotechnologies Grant W911NF-19-2-0026 (B.A.J), 2016 MINT Funds-MIT McGovern Institute for Brain Research, and The Satell Family Foundation (H.A.) Acknowledgments: We thank Dr. George A. Sarkis for his contribution to analysis of the proteomics and Dr. Sarah M. Lewis for SNOTRAP synthesis.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Acetyl-CoA
  • Apoptosis
  • Arsenic
  • Brain cortex
  • Brain disorders
  • Mouse
  • Nitric oxide
  • Nitrosative stress
  • S-nitrosylation
  • Synaptic processes

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