header logo image header logo text
Downloads Login
Research
General Information
ZIRC
ZFIN ID: ZDB-PUB-170111-6
Transgenic Zebrafish Reporter Lines as Alternative in vivo Organ Toxicity Models
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.
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.
ADDITIONAL INFORMATION