Systems toxicology approach for the assessment of zebrafish neurotoxicity

      Li, R.; vom Berg, C.; Talikka, M.; Madan, S.; Dörpinghaus, J.; Szostak, J.; Martin, F.; Peitsch, M. C.; Hoeng, J.; Zupanic, A.
      Conference date
      Mar 12, 2019
      Conference name
      Society of Toxicology (SOT) 2019

      Recent years have seen an unprecedented rise in the use of the zebrafish as a model to study chemical toxicity. This is due in part to external development, amenability to high-throughput assays, rich and defined behavioral repertoire, and compliance with the 3R (replacement, reduction, refinement) initiative. Importantly, chemical toxicity manifests itself in remarkably similar ways in zebrafish and humans. Taking advantage of these benefits, we have selected zebrafish larvae for a comprehensive systems toxicology assessment of the insecticide Imidacloprid. To undertake this assessment, we have developed a biological network model describing neurotoxicity in zebrafish larvae. The model is a computable representation of data curated from scientific literature describing molecular pathways that lead to neurotoxic outcomes in zebrafish. Key signaling nodes in the network model are linked to information about downstream gene expression. Differential expression of downstream genes obtained through transcriptomic analyses can be used to infer activity of the upstream protein. This in turn leads to mechanistic hypothesis generation and gives a quantifiable measure of network perturbation. In parallel to the network approach, we present toxicity results for Imidacloprid according to the Organisation for Economic Co-operation and Development fish embryo toxicity test. We then report results from chemically exposed larvae in behavioral assays. Finally, we describe the utility of the network model in interpreting transcriptomics data to gain mechanistic insight into the molecular events initiated by a given chemical. In conclusion, neurotoxic apical endpoints and computational network scoring provide a comprehensive method for linking molecular events to organ toxicity. This novel method may be applied to toxicological evaluation of chemicals of environmental concern and chemicals of interest in human health as well as chemical mixtures.