An integrative Dictyostelium, C. elegans and zebrafish approach to assess DART

An important goal of toxicity testing is to assess and identify health risks associated with exposure to existing and newly introduced chemicals. Of particular importance is Developmental and Reproductive Toxicity (DART), because of the long-term and delayed characteristics of the toxicity.

DART testing often involves time and money-intensive animal studies. Significant research activity has been focused on the development of alternative testing strategies in non-animal systems like single cells, or in a single non-mammalian multicellular organism, but these studies showed that the data do not provide a complete picture of DART.

Innovative toxicity test systems that enable the identification of the molecular mechanisms that lead to DART and are relevant to humans have the potential to allow improved hazard identification and characterization.

The team, led by Prof Raymond Pieters from the University of Utrecht propose that combinations of test systems are essential for proper DART assessment. In CRACK IT PreDART they exploit the combinatorial power of three distinct non-mammalian organisms (D. rerioC. elegans and D. discoideum). Developmental pathways in these test systems are well-defined, but not yet properly related to DART. Effects of a carefully selected set of compounds responsible for developmental and/or reproduction defects in vertebrates will be thoroughly analysed by phenotype-based pathway identification, assessment of internal concentrations to improve dose-response relationships, and transcriptome and kinome analyses in all test organisms. Results will be aligned for identification of a “key set of response genes” core to induction DART toxicity. These genes will be used to enable establishment of a predictive screening assay for DART defects   

Full details about this CRACK IT Challenge can be found on the CRACK IT website.

Racz P et al. (2017). Application of Caenorhabditis elegans (nematode) and Danio rerio embryo (zebrafish) as model systems to screen for developmental and reproductive toxicity of Piperazine compounds. Toxicology in Vitro doi.org/10.1016/j.tiv.2017.06.002.

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