PUBLICATION

An AOP-based alternative testing strategy to predict the impact of thyroid hormone disruption on swim bladder inflation in zebrafish

Authors
Stinckens, E., Vergauwen, L., Ankley, G.T., Blust, R., Darras, V.M., Villeneuve, D.L., Witters, H., Volz, D.C., Knapen, D.
ID
ZDB-PUB-180428-8
Date
2018
Source
Aquatic toxicology (Amsterdam, Netherlands)   200: 1-12 (Journal)
Registered Authors
Blust, Ronny, Darras, Veerle, Knapen, Dries, Vergauwen, Lucia, Witters, Hilda
Keywords
Adverse outcome pathway, Deiodinase inhibition assay, Swim bladder inflation, Thyroid hormone disruption, Zebrafish embryo
MeSH Terms
  • Air Sacs/drug effects
  • Animals
  • Embryo, Nonmammalian/enzymology
  • Enzyme Assays
  • Enzyme Inhibitors/chemistry
  • Enzyme Inhibitors/metabolism*
  • Enzyme Inhibitors/toxicity
  • Iodide Peroxidase/antagonists & inhibitors
  • Iodide Peroxidase/metabolism
  • Liver/enzymology
  • Swine
  • Thyroid Hormones/metabolism*
  • Thyroxine/chemistry
  • Thyroxine/metabolism
  • Toxicity Tests/methods*
  • Triiodothyronine/chemistry
  • Triiodothyronine/metabolism
  • Water Pollutants, Chemical/chemistry
  • Water Pollutants, Chemical/toxicity
  • Zebrafish/growth & development
  • Zebrafish/physiology*
PubMed
29702435 Full text @ Aquat. Toxicol.
Abstract
The adverse outcome pathway (AOP) framework can be used to help support the development of alternative testing strategies aimed at predicting adverse outcomes caused by triggering specific toxicity pathways. In this paper, we present a case-study demonstrating the selection of alternative in chemico assays targeting the molecular initiating events of established AOPs, and evaluate use of the resulting data to predict higher level biological endpoints. Based on two AOPs linking inhibition of the deiodinase (DIO) enzymes to impaired posterior swim bladder inflation in fish, we used in chemico enzyme inhibition assays to measure the molecular initiating events for an array of 51 chemicals. Zebrafish embryos were then exposed to 14 compounds with different measured inhibition potentials. Effects on posterior swim bladder inflation, predicted based on the information captured by the AOPs, were evaluated. By linking the two datasets and setting thresholds, we were able to demonstrate that the in chemico dataset can be used to predict biological effects on posterior chamber inflation, with only two outliers out of the 14 tested compounds. Our results show how information organized using the AOP framework can be employed to develop or select alternative assays, and successfully forecast downstream key events along the AOP. In general, such in chemico assays could serve as a first-tier high-throughput system to screen and prioritize chemicals for subsequent acute and chronic fish testing, potentially reducing the need for long-term and costly toxicity tests requiring large numbers of animals.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping