PUBLICATION
Arsenic induced redox imbalance triggers the unfolded protein response in the liver of zebrafish
- Authors
- Delaney, P., Ramdas Nair, A., Palmer, C., Khan, N., Sadler, K.C.
- ID
- ZDB-PUB-201120-29
- Date
- 2020
- Source
- Toxicology and applied pharmacology 409: 115307 (Journal)
- Registered Authors
- Delaney, Patrice, Sadler Edepli, Kirsten C.
- Keywords
- Arsenic, ER stress, Liver, Oxidative stress, Unfolded protein response, Zebrafish
- Datasets
- GEO:GSE156420, GEO:GSE156415, GEO:GSE156419, GEO:GSE156412
- MeSH Terms
-
- Reactive Oxygen Species/metabolism
- Animals, Genetically Modified
- Hepatocytes/drug effects
- Hepatocytes/metabolism
- Antioxidants/metabolism
- Larva/drug effects
- Larva/metabolism
- Zebrafish
- Liver/drug effects*
- Liver/metabolism
- Signal Transduction/drug effects
- Oxidative Stress/drug effects
- Arsenic/toxicity*
- Animals
- Unfolded Protein Response/drug effects*
- Endoplasmic Reticulum Stress/drug effects
- Oxidation-Reduction/drug effects*
- PubMed
- 33147493 Full text @ Tox. App. Pharmacol.
- CTD
- 33147493
Citation
Delaney, P., Ramdas Nair, A., Palmer, C., Khan, N., Sadler, K.C. (2020) Arsenic induced redox imbalance triggers the unfolded protein response in the liver of zebrafish. Toxicology and applied pharmacology. 409:115307.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping