PUBLICATION
Characterization of Triptolide-Induced Hepatotoxicity by Imaging and Transcriptomics in a Novel Zebrafish Model
- Authors
- Vliegenthart, A.D.B., Wei, C., Buckley, C., Berends, C., de Potter, C.M.J., Schneemann, S., Del Pozo, J., Tucker, C., Mullins, J.J., Webb, D.J., Dear, J.W.
- ID
- ZDB-PUB-171001-6
- Date
- 2017
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 159: 380-391 (Journal)
- Registered Authors
- Mullins, John
- Keywords
- hepatotoxicity, imaging, microRNA-122, nitric oxide synthase, triptolide, zebrafish
- Datasets
- GEO:GSE146201, GEO:GSE146199, GEO:GSE146200
- MeSH Terms
-
- Animals
- Chemical and Drug Induced Liver Injury/diagnostic imaging*
- Disease Models, Animal*
- Diterpenes/toxicity*
- Epoxy Compounds/toxicity
- Larva/drug effects
- Liver/diagnostic imaging
- Liver/drug effects*
- Liver/metabolism
- Liver/pathology
- MicroRNAs/genetics
- Microscopy, Fluorescence
- Phenanthrenes/toxicity*
- Polymerase Chain Reaction
- Sequence Analysis, RNA
- Transcriptome*
- Zebrafish/genetics
- Zebrafish/growth & development
- PubMed
- 28962522 Full text @ Toxicol. Sci.
- CTD
- 28962522
Citation
Vliegenthart, A.D.B., Wei, C., Buckley, C., Berends, C., de Potter, C.M.J., Schneemann, S., Del Pozo, J., Tucker, C., Mullins, J.J., Webb, D.J., Dear, J.W. (2017) Characterization of Triptolide-Induced Hepatotoxicity by Imaging and Transcriptomics in a Novel Zebrafish Model. Toxicological sciences : an official journal of the Society of Toxicology. 159:380-391.
Abstract
Triptolide is a vine extract used in traditional Chinese medicines and associated with hepatotoxicity. In vitro data suggest that inhibition of RNA synthesis may be the mechanism of toxicity. For studying drug-induced liver injury the zebrafish has experimental, practical and financial advantages compared with rodents. The aim of this study was to explore the mechanism of triptolide toxicity using zebrafish as the model system. The effect of triptolide exposure on zebrafish larvae was determined with regard to mortality, histology, expression of liver specific microRNA-122 and liver volume. Fluorescent microscopy was used to track toxicity in the Tg(-2.8lfabp:GFP)as3 zebrafish line. Informed by microscopy, RNA-sequencing was used to explore the mechanism of toxicity. Triptolide exposure resulted in dose-dependent mortality, a reduction in the number of copies of microRNA-122 per larva, hepatocyte vacuolation, disarray and oncotic necrosis, and a reduction in liver volume. These findings were consistent across replicate experiments. Time-lapse imaging indicated the onset of injury was 6 h after the start of exposure, at which point, RNA-sequencing revealed that 88% of genes were down-regulated. Immune response associated genes were up-regulated in the triptolide-treated larvae including nitric oxide synthase. Inhibition of nitric oxide synthase increased mortality. Triptolide induces hepatotoxicity in zebrafish larvae. This represents a new model of drug-induced liver injury that complements rodents. RNA sequencing, guided by time-lapse microscopy, revealed early down-regulation of genes consistent with previous invitro studies, and facilitated the discovery of mechanistic inflammatory pathways.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping