Pistollato, Francesca, Louisse, Jochem ORCID: 0000-0002-0517-2288, Scelfo, Bibiana ORCID: 0000-0002-2261-8683, Mennecozzi, Milena, Accordi, Benedetta, Basso, Giuseppe, Gaspar, John Antonydas, Zagoura, Dimitra, Barilari, Manuela, Palosaari, Taina, Sachinidis, Agapios and Bremer-Hoffmann, Susanne (2014). Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition. Toxicol. Appl. Pharmacol., 280 (2). S. 378 - 389. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1096-0333

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Abstract

According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2(+) neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. (C) 2014 The Authors. Published by Elsevier Inc.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pistollato, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Louisse, JochemUNSPECIFIEDorcid.org/0000-0002-0517-2288UNSPECIFIED
Scelfo, BibianaUNSPECIFIEDorcid.org/0000-0002-2261-8683UNSPECIFIED
Mennecozzi, MilenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Accordi, BenedettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Basso, GiuseppeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaspar, John AntonydasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zagoura, DimitraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barilari, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palosaari, TainaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sachinidis, AgapiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bremer-Hoffmann, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-425733
DOI: 10.1016/j.taap.2014.08.007
Journal or Publication Title: Toxicol. Appl. Pharmacol.
Volume: 280
Number: 2
Page Range: S. 378 - 389
Date: 2014
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication: SAN DIEGO
ISSN: 1096-0333
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
C-FOS; RESPONSE ELEMENT; X-INACTIVATION; MECHANISMS; EXPRESSION; TOXICITY; DIFFERENTIATION; IDENTIFICATION; CONTRIBUTES; ARRAYMultiple languages
Pharmacology & Pharmacy; ToxicologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42573

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