Comparative Analysis of Zebrafish and Planarian Model Systems for Developmental Neurotoxicity Screens Using an 87-Compound Library

There is a clear need to establish and validate new methodologies to more quickly and efficiently screen chemicals for potential toxic effects, particularly on development. The emergence of alternative animal systems for rapid toxicology screens presents valuable opportunities to evaluate how systems complement each other. In this article, we compare a chemical library of 87-compounds in 2 such systems, developing zebrafish and freshwater planarians, by screening for developmental neurotoxic effects. We show that the systems' toxicological profiles are complementary to each other, with zebrafish yielding more detailed morphological endpoints and planarians more behavioral endpoints. Overall, zebrafish was more sensitive to this chemical library, yielding 86/87 hits, compared with 50/87 hits in planarians. The difference in sensitivity could not be attributed to molecular weight, logK(ow), or the bioconcentration factor. Of the 87 chemicals, 28 had previously been evaluated in mammalian developmental neuro- (DNT), neuro-, or developmental toxicity studies. Of the 28, 20 were hits in the planarian, and 27 were hits in zebrafish. Eighteen of the 28 had previously been identified as DNT hits in mammals and were highly associated with activity in zebrafish and planarian behavioral assays in this study. Only 1 chemical (of 28) was a false negative in both zebrafish and planarian systems. The differences in endpoint coverage and system sensitivity illustrate the value of a dual systems approach to rapidly query a large chemical-bioactivity space and provide weight-of-evidence for prioritization of chemicals for further testing.