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

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.

Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

“…It contributes to multiple physiological and neuropathological processes. Thus, recently, we have shown a reprogramming of the S-nitroso-proteome during the aging process [ 37 ] and in response to arsenic exposure [ 43 ]. Further, we found significant sex differences in the NO and SNO-related biological functions in the cortex [ 33 ].…”

Zinc and Copper Brain Levels and Expression of Neurotransmitter Receptors in Two Rat ASD Models

“…This allowed us to track changes in the distribution of metals in the offspring after a single administration of VPA and THAL to pregnant females compared to the control group. In our studies, we did not examine the effect of a metal deficiency ( Grabrucker et al, 2017 ) or excess ( Amal et al, 2020b ) on the development of an autistic phenotype, but we did examine how the administration of toxins (VPA or THAL) that induced autism-like behavior influenced the distribution of metals in the rat brain. The subject of the study of this work were three regions of the brain: CC, HPC, and CE, because their developmental disorders are particularly strongly associated with ASD pathogenesis ( Varghese et al, 2017 ; Bruchhage et al, 2018 ; Sun et al, 2019 ).…”

Protein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders

“…False positives are by far the worst problem because it introduces misinformation that will confound subsequent systems analysis. A solution to the false-positive problem would be to develop a reagent that would react with and couple to the SNO-site, and this was accomplished by the Tannenbaum laboratory in 2013 (137) and then applied to mouse models of AD (6,138), autism (5), and arsenic toxicity (7). In each case, hundreds to thousands of SNO-proteins were identified in both control and treated mouse frontal cortex.…”

“…Mechanism notwithstanding, this redox-based posttranslational modification (PTM), termed protein S-nitrosylation (SNO), is now well-recognized as a major contributor to both the physiological and pathophysiological activities of ''NO'' (1,5,7,107,138,150). Although the field generally uses the terms protein S-nitrosylation and transnitrosylation (as used here), because a nitroso group is in general being transferred (rather than a nitrosyl group, which is formally an NO radical), chemically the proper terms are S-nitrosation and transnitrosation (148).…”