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Evaluation of transcription factors as biomarkers in a High Content Analysis based in-vitro testing system
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2015 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Developmental neurotoxicological risk assessment of substances is based on extensive and costly animal studies, which ultimately limits the number of substances that can be evaluated. The overall aim of the present study is to investigate if a chosen set of transcription factors (TFs) may be used as biomarkers in a high throughput screening (HTS)-compatible, in-vitro test system for developmental neurotoxicity (DNT) hazard identification. The primary TFs of interest are FosB and JunB. The impact of two substances (Ketamine and BDE-99) with known in-vivo effects on brain development, was evaluated using a mouse multipotent neuronal progenitor cell line (C17.2). The impact on the expression of the TFs was visualized via immunocytochemistry (ICC) and quantitative RT-PCR. The implementation of ICC was designed to allow investigation of the effects of neurotoxicants during different stages of cell development. The employment of qPCR, in turn enabled exploration into the effects of exposure time on cells treated at the beginning of differentiation. Results show that JunB and FosB expression is altered following exposure to either Ketamine or BDE-99. The experiment revealed an increase in the sensitivity of C17.2 cells in later neuronal differentiation stages. The effects on FosB showed to be more distinctive. The qPCR results indicated that the TFs Fyn and cFos, which were additionally evaluated but not with ICC, might be interesting as biomarkers as well because they showed to be affected after a shorter period of exposure than JunB and FosB. In summary, the four TFs JunB, FosB, Fyn and cFos, were found to respond to their respective test substances, providing grounding for further neurotoxicological studies

Place, publisher, year, edition, pages
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Medical and Health Sciences
URN: urn:nbn:se:uu:diva-274220OAI: oai:DiVA.org:uu-274220DiVA: diva2:896063
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Available from: 2016-10-06 Created: 2016-01-20 Last updated: 2016-10-06Bibliographically approved

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