A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays

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• dc.contributor.author Delp, Johannes
• dc.contributor.author Gutbier, Simon
• dc.contributor.author Klima, Stefanie
• dc.contributor.author Hoelting, Lisa
• dc.contributor.author Pinto Gil, Kevin
• dc.contributor.author Hsieh, Jui-Hua
• dc.contributor.author Aichem, Michael
• dc.contributor.author Klein, Karsten
• dc.contributor.author Schreiber, Falk
• dc.contributor.author Tice, Raymond R.
• dc.contributor.author Pastor Maeso, Manuel
• dc.contributor.author Behl, Mamta
• dc.contributor.author Leist, Marcel
• dc.date.accessioned 2019-04-30T07:50:47Z
• dc.date.available 2019-04-30T07:50:47Z
• dc.date.issued 2018
• dc.description.abstract The (developmental) neurotoxicity hazard is still unknown for most chemicals. Establishing a test battery covering most of the relevant adverse outcome pathways may close this gap, without requiring a huge animal experimentation program. Ideally, each of the assays would cover multiple mechanisms of toxicity. One candidate test is the human LUHMES cell-based NeuriTox test. To evaluate its readiness for larger-scale testing, a proof of concept library assembled by the U.S. National Toxicology Program (NTP) was screened. Of the 75 unique compounds, seven were defined as specifically neurotoxic after the hit-confirmation phase and additional ten compounds were generally cytotoxic within the concentration range of up to 20 micromolar. As complementary approach, the library was screened in the PeriTox test, which identifies toxicants affecting the human peripheral nervous system. Of the eight PeriTox hits, five were similar to the NeuriTox hits: rotenone, colchicine, diethylstilbestrol, berberine chloride, and valinomycin. The unique NeuriTox hit, methyl-phenylpyridinium (MPP+) is known from in vivo studies to affect only dopaminergic neurons (which LUHMES cells are). Conversely, the known peripheral neurotoxicant acrylamide was picked up in the PeriTox, but not in the NeuriTox assay. All of the five common hits had also been identified in the published neural crest migration (cMINC) assay, while none of them emerged as cardiotoxicant in a previous screen using the same library. These comparative data suggest that complementary in vitro tests can pick up a broad range of toxicants, and that multiple test results might help to predict organ specificity patterns.
• dc.format.mimetype application/pdf
• dc.identifier.citation Delp J, Gutbier S, Klima S, Hoelting L, Pinto-Gil K, Hsieh JH et al. A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays. ALTEX. 2018;35(2):235-53. DOI: 10.14573/altex.1712182
• dc.identifier.doi http://dx.doi.org/10.14573/altex.1712182
• dc.identifier.issn 1868-596X
• dc.identifier.uri http://hdl.handle.net/10230/37160
• dc.language.iso eng
• dc.publisher Spektrum Akademischer Verlag
• dc.relation.ispartof ALTEX. 2018;35(2):235-53
• dc.rights This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cytotoxicity
• dc.subject.keyword Developmental toxicity
• dc.subject.keyword High content imaging
• dc.subject.keyword Neurite outgrowth inhibition
• dc.subject.keyword Neurotoxicity
• dc.title A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion