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

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...

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Autores: Delp, Johannes, Gutbier, Simon, Klima, Stefanie, Hoelting, Lisa, Pinto Gil, Kevin, Hsieh, Jui-Hua, Aichem, Michael, Klein, Karsten, Schreiber, Falk, Tice, Raymond R., Pastor Maeso, Manuel, Behl, Mamta, Leist, Marcel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/37160
Acceso en línea:http://hdl.handle.net/10230/37160
http://dx.doi.org/10.14573/altex.1712182
Access Level:acceso abierto
Palabra clave:Cytotoxicity
Developmental toxicity
High content imaging
Neurite outgrowth inhibition
Neurotoxicity
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spelling A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assaysDelp, JohannesGutbier, SimonKlima, StefanieHoelting, LisaPinto Gil, KevinHsieh, Jui-HuaAichem, MichaelKlein, KarstenSchreiber, FalkTice, Raymond R.Pastor Maeso, ManuelBehl, MamtaLeist, MarcelCytotoxicityDevelopmental toxicityHigh content imagingNeurite outgrowth inhibitionNeurotoxicityThe (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.Spektrum Akademischer Verlag201920192018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/37160http://dx.doi.org/10.14573/altex.1712182reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésALTEX. 2018;35(2):235-53This 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 citedhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/371602026-06-12T07:21:37Z
dc.title.none.fl_str_mv A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
title A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
spellingShingle A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
Delp, Johannes
Cytotoxicity
Developmental toxicity
High content imaging
Neurite outgrowth inhibition
Neurotoxicity
title_short A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
title_full A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
title_fullStr A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
title_full_unstemmed A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
title_sort A high-throughput approach to identify specific neurotoxicants/ developmental toxicants in human neuronal cell function assays
dc.creator.none.fl_str_mv Delp, Johannes
Gutbier, Simon
Klima, Stefanie
Hoelting, Lisa
Pinto Gil, Kevin
Hsieh, Jui-Hua
Aichem, Michael
Klein, Karsten
Schreiber, Falk
Tice, Raymond R.
Pastor Maeso, Manuel
Behl, Mamta
Leist, Marcel
author Delp, Johannes
author_facet Delp, Johannes
Gutbier, Simon
Klima, Stefanie
Hoelting, Lisa
Pinto Gil, Kevin
Hsieh, Jui-Hua
Aichem, Michael
Klein, Karsten
Schreiber, Falk
Tice, Raymond R.
Pastor Maeso, Manuel
Behl, Mamta
Leist, Marcel
author_role author
author2 Gutbier, Simon
Klima, Stefanie
Hoelting, Lisa
Pinto Gil, Kevin
Hsieh, Jui-Hua
Aichem, Michael
Klein, Karsten
Schreiber, Falk
Tice, Raymond R.
Pastor Maeso, Manuel
Behl, Mamta
Leist, Marcel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cytotoxicity
Developmental toxicity
High content imaging
Neurite outgrowth inhibition
Neurotoxicity
topic Cytotoxicity
Developmental toxicity
High content imaging
Neurite outgrowth inhibition
Neurotoxicity
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/37160
http://dx.doi.org/10.14573/altex.1712182
url http://hdl.handle.net/10230/37160
http://dx.doi.org/10.14573/altex.1712182
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv ALTEX. 2018;35(2):235-53
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Spektrum Akademischer Verlag
publisher.none.fl_str_mv Spektrum Akademischer Verlag
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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