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Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

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DELP, Johannes, Melina FUNKE, Franziska RUDOLF, Andrea CEDIEL, Susanne Hougaard BENNEKOU, Wanda VAN DER STEL, Giada CARTA, Paul JENNINGS, Cosimo TOMA, Marcel LEIST, 2019. Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants. In: Archives of Toxicology. 93(6), pp. 1585-1608. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-019-02473-y

@article{Delp2019-06-12Devel-46030, title={Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants}, year={2019}, doi={10.1007/s00204-019-02473-y}, number={6}, volume={93}, issn={0340-5761}, journal={Archives of Toxicology}, pages={1585--1608}, author={Delp, Johannes and Funke, Melina and Rudolf, Franziska and Cediel, Andrea and Bennekou, Susanne Hougaard and van der Stel, Wanda and Carta, Giada and Jennings, Paul and Toma, Cosimo and Leist, Marcel} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/46030"> <dc:contributor>van der Stel, Wanda</dc:contributor> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2019-06-18T11:14:25Z</dcterms:available> <dc:contributor>Leist, Marcel</dc:contributor> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:creator>Jennings, Paul</dc:creator> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:contributor>Funke, Melina</dc:contributor> <dc:contributor>Bennekou, Susanne Hougaard</dc:contributor> <dc:creator>Funke, Melina</dc:creator> <dc:creator>Leist, Marcel</dc:creator> <dc:creator>Carta, Giada</dc:creator> <dc:creator>Toma, Cosimo</dc:creator> <dc:language>eng</dc:language> <dc:creator>Bennekou, Susanne Hougaard</dc:creator> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/46030/1/Delp_2-144xeglmsuim74.pdf"/> <dc:creator>Rudolf, Franziska</dc:creator> <dcterms:abstract xml:lang="eng">Many neurotoxicants affect energy metabolism in man, but currently available test methods may still fail to predict mito- and neurotoxicity. We addressed this issue using LUHMES cells, i.e., human neuronal precursors that easily differentiate into mature neurons. Within the NeuriTox assay, they have been used to screen for neurotoxicants. Our new approach is based on culturing the cells in either glucose or galactose (Glc-Gal-NeuriTox) as the main carbohydrate source during toxicity testing. Using this Glc-Gal-NeuriTox assay, 52 mitochondrial and non-mitochondrial toxicants were tested. The panel of chemicals comprised 11 inhibitors of mitochondrial respiratory chain complex I (cI), 4 inhibitors of cII, 8 of cIII, and 2 of cIV; 8 toxicants were included as they are assumed to be mitochondrial uncouplers. In galactose, cells became more dependent on mitochondrial function, which made them 2-3 orders of magnitude more sensitive to various mitotoxicants. Moreover, galactose enhanced the specific neurotoxicity (destruction of neurites) compared to a general cytotoxicity (plasma membrane lysis) of the toxicants. The Glc-Gal-NeuriTox assay worked particularly well for inhibitors of cI and cIII, while the toxicity of uncouplers and non-mitochondrial toxicants did not differ significantly upon glucose ↔ galactose exchange. As a secondary assay, we developed a method to quantify the inhibition of all mitochondrial respiratory chain functions/complexes in LUHMES cells. The combination of the Glc-Gal-NeuriTox neurotoxicity screening assay with the mechanistic follow up of target site identification allowed both, a more sensitive detection of neurotoxicants and a sharper definition of the mode of action of mitochondrial toxicants.</dcterms:abstract> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:contributor>Rudolf, Franziska</dc:contributor> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/46030"/> <dc:rights>terms-of-use</dc:rights> <dc:contributor>Cediel, Andrea</dc:contributor> <dc:contributor>Delp, Johannes</dc:contributor> <dc:contributor>Carta, Giada</dc:contributor> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2019-06-18T11:14:25Z</dc:date> <dcterms:title>Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants</dcterms:title> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/46030/1/Delp_2-144xeglmsuim74.pdf"/> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dcterms:issued>2019-06-12</dcterms:issued> <dc:creator>Cediel, Andrea</dc:creator> <dc:creator>Delp, Johannes</dc:creator> <dc:contributor>Toma, Cosimo</dc:contributor> <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/> <dc:contributor>Jennings, Paul</dc:contributor> <dc:creator>van der Stel, Wanda</dc:creator> </rdf:Description> </rdf:RDF>

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