Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs
article
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
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
Topics
Antiepileptic drugsBehaviorDevelopmental (neuro)toxicityGene expressionHistopathologyIntegrated test strategyKineticsZebrafish embryotoxicity test (ZET)Anticonvulsive agentCarbamazepineCytochrome P450 26A1EthosuximideEtiracetamValproic acidALDH1A2 geneAnimal cellAnimal experimentAnimal modelAnimal tissueCase studyCell vacuoleConcentration (parameters)Controlled studyCYP26A1 geneDemo case studyDevelopmental toxicityEdemaEmbryoEmbryotoxicityExperimental designFemaleGeneGene expressionHistopathologyIn situ hybridizationLarvaLiver cellMaleMorphologyMotor activityNerve degenerationNeurotoxicityNonhumanNucleotide sequencePericardial diseasePericardial edemaPhenotypePredictive valueSensitivity analysisSwimmingToxicity testingToxicokineticsWhole mount in situ hybridizationZebra fishZebrafish embryotoxicity test
TNO Identifier
516524
ISSN
08906238
Source
Reproductive Toxicology, 49, pp. 101-116.
Pages
101-116
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