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HERO ID
7455367
Reference Type
Journal Article
Title
Arsenic induced redox imbalance triggers the unfolded protein response in the liver of zebrafish
Author(s)
Delaney, P; Ramdas Nair, A; Palmer, C; Khan, N; Sadler, KC
Year
2020
Is Peer Reviewed?
1
Journal
Toxicology and Applied Pharmacology
ISSN:
0041-008X
EISSN:
1096-0333
Volume
409
Page Numbers
115307
Language
English
PMID
33147493
DOI
10.1016/j.taap.2020.115307
Web of Science Id
WOS:000599506300009
Abstract
Inorganic arsenic (iAs) is one of the most endemic toxicants worldwide and oxidative stress is a key cellular pathway underlying iAs toxicity. Other cellular stress response pathways, such as the unfolded protein response (UPR), are also impacted by iAs exposure, however it is not known how these pathways intersect to cause disease. We optimized the use of zebrafish larvae to identify the relationship between these cellular stress response pathways and arsenic toxicity. We found that the window of iAs susceptibility during zebrafish development corresponds with the development of the liver, and that even a 24-h exposure can cause lethality if administered to mature larvae, but not to early embryos. Acute exposure of larvae to iAs generates reactive oxygen species (ROS), an antioxidant response, endoplasmic reticulum (ER) stress and UPR activation in the liver. An in vivo assay using transgenic larvae expressing a GFP-tagged secreted glycoprotein in hepatocytes (Tg(fabp10a:Gc-EGFP)) revealed acute iAs exposure selectively decreased expression of Gc-EGFP, indicating that iAs impairs secretory protein folding in the liver. The transcriptional output of UPR activation is preceded by ROS production and activation of genes involved in the oxidative stress response. These studies implicate redox imbalance as the mechanism of iAs-induced ER stress and suggest that crosstalk between these pathways underlie iAs-induced hepatic toxicity.
Keywords
Oxidative stress; ER stress; Unfolded protein response; Arsenic; Zebrafish; Liver
Tags
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Arsenic Hazard ID
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