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Whole genome microarray analysis of neural progenitor C17.2 cells during differentiation and validation of 30 neural mRNA biomarkers for estimation of developmental neurotoxicity
Department of Neurochemistry, Stockholm University, Stockholm, Sweden.ORCID iD: 0000-0002-6611-0785
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.ORCID iD: 0000-0003-2775-1632
Department of Neurochemistry, Stockholm University, Stockholm, Sweden; Swetox, Karolinska Institute, Unit of Toxicology Sciences, Södertälje, Sweden.ORCID iD: 0000-0001-6662-0868
Swetox, Karolinska Institute, Unit of Toxicology Sciences, Södertälje, Sweden.ORCID iD: 0000-0003-3107-331X
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2017 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190066Article in journal (Refereed) Published
Abstract [en]

Despite its high relevance, developmental neurotoxicity (DNT) is one of the least studied forms of toxicity. Current guidelines for DNT testing are based on in vivo testing and they require extensive resources. Transcriptomic approaches using relevant in vitro models have been suggested as a useful tool for identifying possible DNT-generating compounds. In this study, we performed whole genome microarray analysis on the murine progenitor cell line C17.2 following 5 and 10 days of differentiation. We identified 30 genes that are strongly associated with neural differentiation. The C17.2 cell line can be differentiated into a co-culture of both neurons and neuroglial cells, giving a more relevant picture of the brain than using neuronal cells alone. Among the most highly upregulated genes were genes involved in neurogenesis (CHRDL1), axonal guidance (BMP4), neuronal connectivity (PLXDC2), axonogenesis (RTN4R) and astrocyte differentiation (S100B). The 30 biomarkers were further validated by exposure to non-cytotoxic concentrations of two DNT-inducing compounds (valproic acid and methylmercury) and one neurotoxic chemical possessing a possible DNT activity (acrylamide). Twenty-eight of the 30 biomarkers were altered by at least one of the neurotoxic substances, proving the importance of these biomarkers during differentiation. These results suggest that gene expression profiling using a predefined set of biomarkers could be used as a sensitive tool for initial DNT screening of chemicals. Using a predefined set of mRNA biomarkers, instead of the whole genome, makes this model affordable and high-throughput. The use of such models could help speed up the initial screening of substances, possibly indicating alerts that need to be further studied in more sophisticated models.

Place, publisher, year, edition, pages
San Francisco: Public Library of Science , 2017. Vol. 12, no 12, article id e0190066
Keywords [en]
C17.2 neurotoxicology
National Category
Biological Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:oru:diva-83157DOI: 10.1371/journal.pone.0190066ISI: 000418564200086PubMedID: 29261810Scopus ID: 2-s2.0-85038819307OAI: oai:DiVA.org:oru-83157DiVA, id: diva2:1440493
Funder
Swedish Research Council FormasKnut and Alice Wallenberg FoundationSwedish Research Council, K2013-79X-21373-05-3Available from: 2018-01-16 Created: 2020-06-15 Last updated: 2021-06-14Bibliographically approved

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Norinder, Ulf

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Attoff, KristinaGliga, AndaLundqvist, JessicaNorinder, UlfForsby, Anna
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