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Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing

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Philipp B. Kuegler1,2, Bastian Zimmer1, Tanja Waldmann1, Birte Baudis1, Sten Ilmjärv3,4, Jürgen Hescheler5, Phil Gaughwin6, Patrik Brundin7, William Mundy8, Anna K. Bal-Price9, André Schrattenholz10, Karl-Heinz Krause11, Christoph van Thriel12, Mahendra S. Rao13, Suzanne Kadereit1 and Marcel Leist1
1 Doerenkamp-Zbinden Chair for in vitro toxicology and Biomedicine, University of Konstanz, Germany;
2 Konstanz Research School Chemical Biology, University of Konstanz, Germany;
3 Quretec, Tartu, Estonia;
4 Department of Physiology, University of Tartu, Estonia;
5 Institute of Neurophysiology, University of Cologne, Germany;
6 Stem Cell and Developmental Biology, Genome Institute of Singapore;
7 Department of Experimental Medical Science, Wallenberg Neuroscience Center, Sweden;
8 Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, USEPA, NC, USA;
9 European Centre for the Validation of Alternative Methods, Institute of Health and Consumer Protection, JRC, Ispra, Italy;
10 ProteoSys, Mainz, Germany;
11 Department of Genetic and Laboratory Medicine, Geneva University Hospitals, Switzerland;
12 Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund, Germany;
13 Life Technologies, Frederick, MD, USA

Summary

Developmental neurotoxicity (DNT) is a serious concern for environmental chemicals, as well as for food and drug constituents. Animal-based DNT models have relatively low sensitivity, and they are burdened by high work-load, cost and animal ethics. Murine embryonic stem cells (mESC) recapitulate several critical processes involved in the development of the nervous system if they are induced to differentiate into neural cells. They therefore represent an alternative toxicological model to predict human hazard. In this review, we discuss how mESC can be used for DNT assays. We have compiled a list of mRNA markers that define undifferentiated mESC (n = 42), neural stem cells (n = 73), astrocytes (n = 25) and the pattern of different neuronal and non-neuronal cell types generated (n = 57). We propose that transcriptional profiling can be used as a sensitive endpoint in toxicity assays to distinguish neural differentiation states during normal and disturbed development. Importantly, we believe that it can be scaled up to relatively high throughput whilst still providing rich information on disturbances affecting small cell subpopulations. Moreover, this approach can provide insight into underlying mechanisms and pathways of toxicity. We broadly discuss the methodological basis of marker lists and DNT assay design. The discussion is put in the context of a new generation of alternative assays (embryonic stem cell based DNT testing = ESDNT V2.0), that may later include human induced pluripotent stem cells, and that are not designed for 1:1 replacement of animal experiments, but are rather intended to improve human risk assessment by using independent scientific principles.


ALTEX 27(1), 16-41

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