Journal
REPRODUCTIVE TOXICOLOGY
Volume 49, Issue -, Pages 101-116Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.reprotox.2014.07.082
Keywords
Zebrafish embryotoxicity test (ZET); Developmental (neuro)toxicity; Antiepileptic drugs; Integrated test strategy; Histopathology; Kinetics; Behavior; Gene expression
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Funding
- Netherlands Toxicogenomics Center (NTC)
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To improve the predictability of the zebrafish embryotoxicity test (ZET) for developmental (neuro)toxicity screening, we used a multiple-endpoints strategy, including morphology, motor activity (MA), histopathology and kinetics. The model compounds used were antiepileptic drugs (AEDs): valproic acid (VPA), carbamazepine (CBZ), ethosuximide (ETH) and levetiracetam (LEV). For VPA, histopathology was the most sensitive parameter, showing effects already at 60 mu M. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180 mu M. For ETH, all endpoints showed similar sensitivity (6.6 mM), whereas MA was the most sensitive parameter for LEV (40 mM). Inclusion of kinetics did not alter the absolute ranking of the compounds, but the relative potency was changed considerably. Taking all together, this demo-case study showed that inclusion of multiple-endpoints in ZET may increase the sensitivity of the assay, contribute to the elucidation of the mode of toxic action and to a better definition of the applicability domain of ZET. (C) 2014 Elsevier Inc. All rights reserved.
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