Rotenone exerts developmental neurotoxicity in a human brain spheroid model

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PAMIES, David, Katharina BLOCK, Pierre LAU, Laura GRIBALDO, Carlos A. PARDO, Paula BARRERAS, Lena SMIRNOVA, Daphne WIERSMA, Liang ZHAO, Thomas HARTUNG, 2018. Rotenone exerts developmental neurotoxicity in a human brain spheroid model. In: Toxicology and Applied Pharmacology. 354, pp. 101-114. ISSN 0041-008X. eISSN 1096-0333. Available under: doi: 10.1016/j.taap.2018.02.003

@article{Pamies2018-09Roten-41790, title={Rotenone exerts developmental neurotoxicity in a human brain spheroid model}, year={2018}, doi={10.1016/j.taap.2018.02.003}, volume={354}, issn={0041-008X}, journal={Toxicology and Applied Pharmacology}, pages={101--114}, author={Pamies, David and Block, Katharina and Lau, Pierre and Gribaldo, Laura and Pardo, Carlos A. and Barreras, Paula and Smirnova, Lena and Wiersma, Daphne and Zhao, Liang and Hartung, Thomas} }

<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/123456789/41790"> <dc:creator>Smirnova, Lena</dc:creator> <dc:language>eng</dc:language> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:creator>Barreras, Paula</dc:creator> <dc:contributor>Hartung, Thomas</dc:contributor> <dc:creator>Block, Katharina</dc:creator> <dc:contributor>Smirnova, Lena</dc:contributor> <dcterms:title>Rotenone exerts developmental neurotoxicity in a human brain spheroid model</dcterms:title> <dc:contributor>Block, Katharina</dc:contributor> <dc:creator>Zhao, Liang</dc:creator> <dc:contributor>Pardo, Carlos A.</dc:contributor> <dc:contributor>Barreras, Paula</dc:contributor> <dc:contributor>Zhao, Liang</dc:contributor> <dc:creator>Gribaldo, Laura</dc:creator> <dc:contributor>Pamies, David</dc:contributor> <dc:contributor>Wiersma, Daphne</dc:contributor> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2018-03-15T08:17:04Z</dcterms:available> <dc:creator>Pamies, David</dc:creator> <dc:contributor>Lau, Pierre</dc:contributor> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/41790"/> <dcterms:issued>2018-09</dcterms:issued> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2018-03-15T08:17:04Z</dc:date> <dc:creator>Lau, Pierre</dc:creator> <dc:creator>Hartung, Thomas</dc:creator> <dc:creator>Wiersma, Daphne</dc:creator> <dc:contributor>Gribaldo, Laura</dc:contributor> <dc:creator>Pardo, Carlos A.</dc:creator> <dcterms:abstract xml:lang="eng">Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and NT assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predict and study human toxicity. By combining these technologies, we generated multicellular brain spheroids (BrainSpheres) from human iPSC. The model has previously shown to be reproducible and recapitulates several neurodevelopmental features. Our results indicate, rotenone's toxic potency varies depending on the differentiation status of the cells, showing higher reactive oxygen species (ROS) and higher mitochondrial dysfunction during early than later differentiation stages. Immuno-fluorescence morphology analysis after rotenone exposure indicated dopaminergic-neuron selective toxicity at non-cytotoxic concentrations (1 μM), while astrocytes and other neuronal cell types were affected at (general) cytotoxic concentrations (25 μM). Omics analysis showed changes in key pathways necessary for brain development, indicating rotenone as a developmental neurotoxicant and show a possible link between previously shown effects on neurite outgrowth and presently observed effects on Ca2+ reabsorption, synaptogenesis and PPAR pathway disruption. In conclusion, our BrainSpheres model has shown to be a reproducible and novel tool to study neurotoxicity and developmental neurotoxicity. Results presented here support the idea that rotenone can potentially be a developmental neurotoxicant.</dcterms:abstract> </rdf:Description> </rdf:RDF>

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