PUBLICATION

Transgenic Zebrafish Reporter Lines as Alternative in vivo Organ Toxicity Models

Authors
Poon, K.L., Wang, X., Lee, S.G., Ng, A.S., Goh, W.H., Zhao, Z., Al-Haddawi, M., Wang, H., Mathavan, S., Ingham, P.W., Mcginnis, C., Carney, T.J.
ID
ZDB-PUB-170111-6
Date
2017
Source
Toxicological sciences : an official journal of the Society of Toxicology   156(1): 133-148 (Journal)
Registered Authors
Carney, Tom, Ingham, Philip, Poon, Kar Lai, Wang, Xingang, Zhao, Zhonghua
Keywords
Zebrafish, biomarker, hepatotoxicity, toxicology, transgenesis
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Biomarkers/metabolism
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical/methods*
  • Drugs, Investigational/administration & dosage
  • Drugs, Investigational/adverse effects*
  • Endoderm/drug effects
  • Endoderm/growth & development
  • Endoderm/metabolism
  • Female
  • Fish Proteins/genetics
  • Fish Proteins/metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental/drug effects*
  • Genes, Reporter/drug effects*
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Larva/drug effects
  • Larva/genetics
  • Larva/growth & development
  • Larva/metabolism
  • Liver/drug effects*
  • Liver/growth & development
  • Liver/metabolism
  • Male
  • Organogenesis/drug effects
  • Recombinant Proteins/metabolism
  • Teratogens/toxicity
  • Toxicity Tests/methods*
  • Xenobiotics/administration & dosage
  • Xenobiotics/toxicity*
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed
28069987 Full text @ Toxicol. Sci.
Abstract
Organ toxicity, particularly liver toxicity, remains one of the major reasons for termination of drug candidates in the development pipeline as well as withdrawal or restrictions of marketed drugs. A screening-amenable alternative in vivo model such as zebrafish would therefore find immediate application in the early prediction of unacceptable organ toxicity. To identify highly upregulated genes as biomarkers of toxic responses in the zebrafish model, a set of well-characterized reference drugs that cause drug induced liver injury (DILI) in the clinic were applied to zebrafish larvae and adults. Transcriptome microarray analysis was performed on whole larvae or dissected adult livers. Integration of data sets from different drug treatments at different stages identified common upregulated detoxification pathways. Within these were candidate biomarkers which recurred in multiple treatments. We prioritized four highly upregulated genes encoding enzymes acting in distinct phases of the drug metabolism pathway. Through promoter isolation and fosmid recombineering, eGFP reporter transgenic zebrafish lines were generated and evaluated for their response to DILI drugs. Three of the four generated reporter lines showed a dose and time dependent induction in endodermal organs to reference drugs and an expanded drug set. In conclusion, through integrated transcriptomics and transgenic approaches, we have developed parallel independent zebrafish in vivo screening platforms able to predict organ toxicities of preclinical drugs.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes