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dc.contributor.authorde Leeuw, Victoria C
dc.contributor.authorvan Nieuwland, Marieke
dc.contributor.authorBokkers, Bas G H
dc.contributor.authorPiersma, Aldert H
dc.date.accessioned2020-10-13T07:22:15Z
dc.date.available2020-10-13T07:22:15Z
dc.date.issued2020-10-09
dc.identifier.issn0261-1929
dc.identifier.pmid33034509
dc.identifier.doi10.1177/0261192920961963
dc.identifier.urihttp://hdl.handle.net/10029/624437
dc.description.abstractIn vitro tests are increasingly applied in chemical hazard assessment. Basic culture conditions may affect the outcome of in vitro tests and should be optimised to reduce false predictions. The neural embryonic stem cell test (ESTn) can predict early neurodevelopmental effects of chemicals, as it mimics the differentiation of stem cells towards the neuroectodermal lineage. Normal early neural differentiation depends crucially on folic acid (FA) and methionine (MET), both elements of the one-carbon (1C) cycle. The aim of this study was to assess the concentration-dependent influence of FA and MET on neural differentiation in the ESTn, and its consequences for assay sensitivity to methotrexate (MTX), a compound that interferes with the 1C cycle. Neural differentiation was inhibited below 0.007 mM and above 0.22 mM FA, while both stem cell viability (< 0.097 mM, > 1.52 mM) and neural differentiation (< 0.181 mM, > 1.35 mM) were affected when changing MET concentrations. A 10-day exposure to 13 nM MTX inhibited neural differentiation, especially in FA- and MET-deficient conditions. However, a 24-hour exposure to 39 nM MTX decreased neural cell and neural crest cell differentiation markers only when the concentration of FA in the medium was three times the standard concentration, which was expected to have a protective effect against MTX. These results show the importance of nutrient concentrations, exposure scenarios and timing of read-outs for cell differentiation and compound sensitivity in the ESTn. Caution should be taken when interpreting results from a single in vitro test, especially when extrapolating to effects on complex morphogenetic processes, like neural tube development.en_US
dc.language.isoenen_US
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectdevelopmental neurotoxicityen_US
dc.subjectdevelopmental toxicityen_US
dc.subjectembryonic stem cellsen_US
dc.subjectfolic aciden_US
dc.subjectin vitroen_US
dc.subjectmethionineen_US
dc.subjectmethotrexateen_US
dc.titleCulture Conditions Affect Chemical-Induced Developmental Toxicity : The Case of Folic Acid, Methionine and Methotrexate in the Neural Embryonic Stem Cell Test.en_US
dc.typeArticleen_US
dc.identifier.journalAltern Lab Animal 2020; 48(4):173-83en_US
dc.source.journaltitleAlternatives to laboratory animals : ATLA


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