Assessment of the developmental neurotoxicity of compounds by measuring locomotor activity in zebrafish embryos and larvae

Abstract

The developmental neurotoxic potential of the majority of environmental chemicals and drugs is currently undetermined. Specific in vivo studies provide useful data for hazard assessment but are not amenable to screen thousands of untested compounds. In this study, methods which use zebrafish embryos, eleutheroembryos and larvae as model organisms, were proposed as alternatives for developmental neurotoxicity (DNT) testing. The evaluation of spontaneous tail coilings in zebrafish embryos aged 24-26 hours post fertilization (hpf) and the swimming activity of eleutheroembryos at 120 and larvae at 144 hpf, i.e. parameters for locomotor activity, were investigated as potential endpoints for DNT testing, according to available standard protocols. The overall performance and predictive value of these methods was then examined by testing a training set of 10 compounds, including known developmental neurotoxicants and compounds not considered to be neurotoxic. The classification of the selected compounds as either neurotoxic or non-neurotoxic, based on the effects observed in zebrafish embryos and larvae, was compared to available mammalian data and an overall concordance of 90% was achieved. Furthermore, the specificity of the selected endpoints for DNT was evaluated as well as the potential similarities between zebrafish and mammals with regard to mechanisms of action for the selected compounds. Although further studies, including the screening of a large testing set of compounds are required, we suggest that the proposed methods with zebrafish embryos and larvae might be valuable alternatives for animal testing for the screening and prioritization of compounds for DNT.