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Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs

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Author: Beker van Woudenberg, A. · Snel, C. · Rijkmans, E. · Groot, D. de · Bouma, M. · Hermsen, S. · Piersma, A. · Menke, A. · Wolterbeek, A.
Type:article
Date:2014
Source:Reproductive Toxicology, 49, 101-116
Identifier: 516524
doi: doi:10.1016/j.reprotox.2014.07.082
Keywords: Biology · Antiepileptic drugs · Behavior · Developmental (neuro)toxicity · Gene expression · Histopathology · Integrated test strategy · Kinetics · Zebrafish embryotoxicity test (ZET) · Anticonvulsive agent · Carbamazepine · Cytochrome P450 26A1 · Ethosuximide · Etiracetam · Valproic acid · ALDH1A2 gene · Animal cell · Animal experiment · Animal model · Animal tissue · Case study · Cell vacuole · Concentration (parameters) · Controlled study · CYP26A1 gene · Demo case study · Developmental toxicity · Edema · Embryo · Embryotoxicity · Experimental design · Female · Gene · Gene expression · Histopathology · In situ hybridization · Larva · Liver cell · Male · Morphology · Motor activity · Nerve degeneration · Neurotoxicity · Nonhuman · Nucleotide sequence · Pericardial disease · Pericardial edema · Phenotype · Predictive value · Sensitivity analysis · Swimming · Toxicity testing · Toxicokinetics · Whole mount in situ hybridization · Zebra fish · Zebrafish embryotoxicity test · Biomedical Innovation · Healthy Living · Life · RAPID - Risk Assessment Products in Development · ELSS - Earth, Life and Social Sciences

Abstract

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. μM. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180. μM. 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. © 2014 Elsevier Inc. Molecular Sequence Numbers: GENBANK: NM_131146, NM_131850; Chemicals/CAS: carbamazepine, 298-46-4, 8047-84-5; ethosuximide, 77-67-8; etiracetam, 102767-28-2, 33996-58-6; valproic acid, 1069-66-5, 99-66-1 Manufacturers: Sigma Aldrich, United States