Strengths and limitations of the worm Development and Activity Test (wDAT) as a chemical screening tool for developmental hazards

Abstract

The worm Development and Activity Test (wDAT) measures C. elegans developmental milestone acquisition timing and stage-specific spontaneous locomotor activity (SLA). Previously, the wDAT identified developmental delays and SLA level changes in C. elegans with mammalian developmental toxicants arsenic, lead, and mercury. 5-fluorouracil (5FU), cyclophosphamide (CP), hydroxyurea (HU), and ribavirin (RV) are teratogens that also induce growth retardation in developing mammals. In at least some studies on each of these chemicals, fetal weight reductions were seen at mammalian exposures below those that had teratogenic effects, suggesting that screening for developmental delay in a small alternative whole-animal model could act as a general toxicity endpoint to identify chemicals for further testing for more specific adverse developmental outcomes. Consistent with mammalian developmental effects, 5FU, HU, and RV were associated with developmental delays with the wDAT. Exposures associated with developmental delay induced hypoactivity with 5FU and HU, but slight hyperactivity with RV. CP is a prodrug that requires bioactivation by cytochrome P450s for both therapeutic and toxic effects. CP tests as a false negative in several in vitro assays, and it was also a false negative with the wDAT. These results suggest that the wDAT has the potential to identify some developmental toxicants, and that a positive wDAT result with an unknown may warrant further testing in mammals. Further assessment with larger panels of positive and negative controls will help qualify the applicability and utility of this C. elegans wDAT assay within toxicity test batteries or weight of evidence approaches for developmental toxicity assessment.