title: Zebrafish embryotoxicity test for developmental (neuro)toxicity: Demo case of an integrated screening approach system using anti-epileptic drugs.
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 60μM. For CBZ, morphology and MA were the most sensitive parameters, showing effects at 180μM. For ETH, all endpoints showed similar sensitivity (6.6mM), whereas MA was the most sensitive parameter for LEV (40mM). 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.
authors.affiliation: TNO, Research Group Risk Analysis for Products In Development (RAPID), Zeist, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Beker van Woudenberg
authors.affiliation: TNO Triskelion B.V., Zeist, The Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Snel
authors.affiliation: TNO, Research Group Risk Analysis for Products In Development (RAPID), Zeist, The Netherlands.
authors.forename: Eke
authors.initials: E
authors.lastname: Rijkmans
authors.affiliation: TNO, Research Group Risk Analysis for Products In Development (RAPID), Zeist, The Netherlands.
authors.forename: Didima
authors.initials: D
authors.lastname: de Groot
authors.affiliation: TNO, Research Group Risk Analysis for Products In Development (RAPID), Zeist, The Netherlands.
authors.forename: Marga
authors.initials: M
authors.lastname: Bouma
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Hermsen
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Aldert
authors.initials: A
authors.lastname: Piersma
authors.affiliation: TNO Triskelion B.V., Zeist, The Netherlands.
authors.forename: Aswin
authors.initials: A
authors.lastname: Menke
authors.affiliation: TNO, Research Group Risk Analysis for Products In Development (RAPID), Zeist, The Netherlands. Electronic address: andre.wolterbeek@tno.nl.
authors.forename: André
authors.initials: A
authors.lastname: Wolterbeek
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000196:embryology; D002220:Carbamazepine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005013:Ethosuximide / Q000633:toxicity; D017403:In Situ Hybridization; D000077287:Levetiracetam; D010889:Piracetam / Q000031:analogs & derivatives / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods; D014635:Valproic Acid / Q000633:toxicity; D015027:Zebrafish / Q000196:embryology*
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D000077287:Levetiracetam; D005013:Ethosuximide; D014635:Valproic Acid; D010889:Piracetam
keywords: Antiepileptic drugs; Behavior; Developmental (neuro)toxicity; Gene expression; Histopathology; Integrated test strategy; Kinetics; Zebrafish embryotoxicity test (ZET)