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Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing
Citation:
Kuegler, P., B. Zimmer, T. Waldman, B. Baudis, S. Ilmjarv, J. Hescheler, E. Fritscher, P. Gaughwin, P. Brundin, W. R. MUNDY, K. Karl-Heinz, A. K. Bal-Price, C. van Thriell, M. S. Rao, S. Kadereit, AND M. Leist. Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing. ALTEX. Society ALTEX Edition, Kuesnacht, Switzerland, 27(1):17-42, (2010).
Impact/Purpose:
In vitro test methods can provide a rapid approach for the screening of large numbers of chemicals for their potential to produce toxicity (hazard identification). Such screening could facilitate prioritization of resources needed for in vivo toxicity testing towards those chemicals most likely to result in adverse health effects. Murine embryonic stem cells (mESC) that differentiate to neural cells recapitulate all developmental steps known from the development of the nervous system. They may therefore be used as alternative toxicological model to predict human hazard. Different approaches towards the use of mESC for DNT assays are discussed here, especially in the context of a modem mechanism-and pathway-based toxicology. Transcriptional profiling is suggested as sensitive endpoint that can be scaled up to relatively high throughput, but still gives rich information on underlying mechanisms oftoxicity and disturbances affecting small subpopulations. The goal of this review is to provide a listing of genes that can be used as markers for the differentiation and maturation of mESC to mNSC and to neurons and glia.
Description:
Developmental neurotoxicity (DNT) is a significant concern for environmental chemicals, as well as for food and drug constituents. The sensitivity of animal-based DNT models is unclear, and they are expensive and time consuming. Murine embryonic stem cells (mESC) recapitulate several critical processes involved in the development of the nervous system when they are induced to differentiate into neural cells. They therefore represent a potential 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 altered development. Importantly, we believe that it can be scaled to a relatively high throughput whilst still providing a rich data set on disturbances affecting small cell subpopulations. Moreover, this approach can provide insight into underlying mechanisms and toxicity pathways. 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 and 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.
