Editor's Highlight: Transgenic Zebrafish Reporter Lines as Alternative In Vivo Organ Toxicity Models

Kar Lai Poon, Xingang Wang, Serene G P Lee, Ashley S Ng, Wei Huang Goh, Zhonghua Zhao, Muthafar Al-Haddawi, Haishan Wang, Sinnakaruppan Mathavan, Philip W Ingham, Claudia McGinnis, Tom J Carney

Research output: Contribution to journalArticlepeer-review

24 Citations (SciVal)

Abstract

Organ toxicity, particularly liver toxicity, remains one of the major reasons for the 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 4 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 4 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.

Original languageEnglish
Pages (from-to)133-148
Number of pages16
JournalToxicological Sciences
Volume156
Issue number1
Early online date10 Jan 2017
DOIs
Publication statusPublished - 1 Mar 2017

Bibliographical note

© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Keywords

  • Animals
  • Animals, Genetically Modified
  • Biomarkers/metabolism
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical/methods
  • Drugs, Investigational/administration & dosage
  • Endoderm/drug effects
  • Female
  • Fish Proteins/genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental/drug effects
  • Genes, Reporter/drug effects
  • Green Fluorescent Proteins/genetics
  • Larva/drug effects
  • Liver/drug effects
  • Male
  • Organogenesis/drug effects
  • Recombinant Proteins/metabolism
  • Teratogens/toxicity
  • Toxicity Tests/methods
  • Xenobiotics/administration & dosage
  • Zebrafish/genetics

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