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Neurofunctional endpoints assessed in human neuroblastoma SH-SY5Y cells for estimation of acute systemic toxicity
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-6867-8123
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-6662-0868
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
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2010 (Engelska)Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 245, nr 2, s. 191-202Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The objective of the EU-funded integrated project ACuteTox is to develop a strategy in which general cytotoxicity, together with organ-specific toxicity and biokinetic features, are used for the estimation of human acute systemic toxicity. Our role in the project is to characterise the effect of reference chemicals with regard to neurotoxicity. We studied cell membrane potential (CMP), noradrenalin (NA) uptake, acetylcholine esterase (AChE) activity, acetylcholine receptor (AChR) signalling and voltage-operated calcium channel (VOCC) function in human neuroblastoma SH-SY5Y cells after exposure to 23 pharmaceuticals, pesticides or industrial chemicals. Neurotoxic alert chemicals were identified by comparing the obtained data with cytotoxicity data from the neutral red uptake assay in 3T3 mouse fibroblasts. Furthermore, neurotoxic concentrations were correlated with estimated human lethal blood concentrations (LC50). The CMP assay was the most sensitive assay, identifying eight chemicals as neurotoxic alerts and improving the LC50 correlation for nicotine, lindane, atropine and methadone. The NA uptake assay identified five neurotoxic alert chemicals and improved the LC50 correlation for atropine, diazepam, verapamil and methadone. The AChE, AChR and VOCC assays showed limited potential for detection of acute toxicity. The CMP assay was further evaluated by testing 36 additional reference chemicals. Five neurotoxic alert chemicals were generated and orphendrine and amitriptyline showed improved LC50 correlation. Due to the high sensitivity and the simplicity of the test protocol, the CMP assay constitutes a good candidate assay to be included in an in vitro test strategy for prediction of acute systemic toxicity.

Ort, förlag, år, upplaga, sidor
2010. Vol. 245, nr 2, s. 191-202
Nyckelord [en]
ACuteTox, Acute toxicity, Neurotoxicity In vitro, SH-SY5Y
Nationell ämneskategori
Biologiska vetenskaper Kemi
Forskningsämne
neurokemi med molekylär neurobiologi
Identifikatorer
URN: urn:nbn:se:su:diva-50346DOI: 10.1016/j.taap.2010.02.018ISI: 000278083100006PubMedID: 20211194OAI: oai:DiVA.org:su-50346DiVA, id: diva2:380855
Forskningsfinansiär
EU, Europeiska forskningsrådet, LSHB-CT-2004-512051
Anmärkning

authorCount :6

Tillgänglig från: 2010-12-22 Skapad: 2010-12-22 Senast uppdaterad: 2018-01-22Bibliografiskt granskad
Ingår i avhandling
1. Neuroblastoma SH-SY5Y and neural progenitor C17.2 cell lines as models for neurotoxicological studies​
Öppna denna publikation i ny flik eller fönster >>Neuroblastoma SH-SY5Y and neural progenitor C17.2 cell lines as models for neurotoxicological studies​
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

We are surrounded by chemicals, thus understanding how exposure to these chemicals affect us during our life is of great social importance. In order to predict human acute toxicity of chemicals, cosmetics or drugs, development of novel in vitro test strategies is required. The overall aim of this thesis was to evaluate whether two different cell line models could be used to predict acute neurotoxicity or developmental neurotoxicity. In paper one, we identified changes in cell membrane potential (CMP) as the most sensitive indicator of toxicity in neuroblastoma SH-SY5Y cells.

In the following studies, we evaluated the capacity of the murine neural progenitor cell line C17.2 to differentiate into mixed cell cultures. Upon differentiation of the C17.2 cells we could identify two morphologically distinguishable cell types; astrocytes and neurons (Paper II). We then investigated how differentiated C17.2 cells responded to non-cytotoxic concentrations of three known neurotoxic and three non-neurotoxic substances. The neurotoxicants induced depolarisation of CMP and alteration in the mRNA expression of at least one of the three biomarkers studied, i.e. βIII-tubulin, glial fibrillary acidic protein or heat shock protein-32. In contrast, no significant effects were observed when exposed to non-neurotoxic compounds (Paper IV).

To further characterise the C17.2 cell model during differentiation, an mRNA microarray analysis of the whole genome was performed. The 30 most significantly altered biomarkers with association to neuronal development were identified. The mRNA expression of the 30 biomarkers were used as a panel to alert for developmental neurotoxicity by exposing C17.2 cells during differentiation to toxicants known to induce impaired nervous system development. All but two of the selected genes were significantly altered by at least one of the chemicals, but none of the 30 genes were affected when treated with the negative control (Paper III).  

In conclusion, the differentiated C17.2 neural progenitor cell line seems to be an attractive model for studying and predicting acute and developmental neurotoxicity. 

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Neurochemistry, Stockholm University, 2018. s. 84
Nyckelord
SH-SY5Y, C17.2, in vitro neurotoxicity, cell culture conditions, biomarkers, in vitro developmental neurotoxicity, whole genome microarray
Nationell ämneskategori
Kemi
Forskningsämne
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-151654 (URN)978-91-7797-108-5 (ISBN)978-91-7797-109-2 (ISBN)
Disputation
2018-03-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-02-07 Skapad: 2018-01-17 Senast uppdaterad: 2020-05-07Bibliografiskt granskad

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Av författaren/redaktören
Gustafsson, HelenaRunesson, JohanLundqvist, JessicaForsby, Anna
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Institutionen för neurokemi
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Toxicology and Applied Pharmacology
Biologiska vetenskaperKemi

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