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Gene expression as a sensitive endpoint to evaluate cell differentiation andmaturation of the developing central nervous system in primary cultures of ratcerebellar granule cells (CGCs) exposed to pesticides
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
In vitro toxicology unit.
Traceability, Risk and Vulnerability Assessment.
In vitro toxicology unit.
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2009 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, Vol. 235, 268-286 p.Article in journal (Refereed) Published
Abstract [en]

The major advantage of primary neuronal cultures for developmental neurotoxicity (DNT) testing is their ability to replicate the crucial stages of neurodevelopment. In our studies using primary culture of cerebellar granule cells (CGCs) we have evaluated whether the gene expression relevant to the most critical developmental processes such as neuronal differentiation (NF-68 and NF-200) and functional maturation (NMDA and GABA presence of neural precursor cells (nestin and Sox10) could be used as an endpoint for in vitro DNT. The expression of these genes was assessed after exposure to various pesticides (paraquat parathion, dichlorvos, pentachlorophenol and cycloheximide) that could induce developmental neurotoxicity through different mechanisms. All studied pesticides signi different stages of neuronal and/or glial cell development and maturation. The most signi observed after exposure to paraquat and parathion (i.e. down-regulation of mRNA expression of NF-68 and NF-200, NMDA and GABA expression of NF-68 and GABA as signi astrocyte marker (S100 multiple pathways of neurodevelopment can be identi in different stages of cell development and maturation, and that gene expression could be used as a sensitive endpoint for initial screening to identify the compounds with the potential to cause developmental neurotoxicity. A receptors), proliferation and differentiation of astrocytes (GFAP and S100β) as well as theficantly modified the expression of selected genes, related to theficant changes wereA receptors). Similarly, dichlorvos affected mainly neurons (decreased mRNAA receptors) whereas cycloheximide had an effect on neurons and astrocytes,ficant decreases in the mRNA expression of both neurofilaments (NF-68 and NF-200) and theβ) were observed. Our results suggest that toxicity induced by pesticides that targetfied by studying expression of genes that are involved

Place, publisher, year, edition, pages
2009. Vol. 235, 268-286 p.
URN: urn:nbn:se:su:diva-30071DOI: 10.1016/j.taap.2008.12.014ISI: 000264207900002OAI: diva2:241168
Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2009-10-01Bibliographically approved
In thesis
1. Developmental Neurotoxicity Testing Using In vitro Approaches
Open this publication in new window or tab >>Developmental Neurotoxicity Testing Using In vitro Approaches
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a great concern about children’s health as the developing brain in foetuses and children is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that the adult brain is well protected against chemicals by the blood brain barrier (BBB) and children have increased absorption rates and diminished ability to detoxify many exogenous compounds, in comparison to that of adults. Moreover, the development of the central nervous system (CNS) is a very complex process involving several different important events, e.g. proliferation, migration and differentiation of cells. These events are occurring within a strictly controlled time frame and therefore create different windows of vulnerability. Furthermore, the brain consists of numerous different cell types (neuronal, glial and endothelial cells) that have specific functions. The development of each cell type occurs within a specific time window and is therefore susceptible to environmental disturbances at different time periods.

Evidence indicates that exposure to industrial chemicals, pesticides or drugs, contributes to the increasing incidence of neurodevelopment disorders. However, due to lack of studies only a few industrial chemicals have been identified as developmental neurotoxicants so far. The current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and US EPA 712-C-98-239) are based entirely on in vivo studies that are time consuming, complex, costly and not suitable for the testing of a high number of chemicals. Applying alternative approaches such as in silico, in vitro and non-mammalian models as a part of an integrated test strategy, could speed up the process of DNT evaluation and reduce and refine animal usage. Both in vitro and non-mammalian test systems offer the possibility of providing an early screening for a large number of chemicals, and could be particularly useful in characterising the compound-induced mechanism of toxicity of various developmental processes.

This thesis has characterised two primary neuronal cultures (cerebellar granule cells (CGCs) and cortical neuronal cultures) and identified them as relevant models for DNT testing, since the key processes of brain development are present, such as cell proliferation, migration and neuronal/glial differentiation. Furthermore, two emerging technologies (gene expression and electrical activity) have been evaluated and were identified as promising tools for in vitro DNT assessment. In combination with other assays they could be included into a DNT intelligent testing strategy to speed up the process of DNT evaluation mainly by prioritising chemicals with DNT potential for further testing.

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2009. 64 p.
National Category
Pharmacology and Toxicology
Research subject
urn:nbn:se:su:diva-30056 (URN)978-91-7155-941-8 (ISBN)
Public defence
2009-10-30, sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 10:00 (English)
The work of this thesis was performed at ECVAM, European Commission, Italy. At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: In progress. Paper 4: In progress. Available from: 2009-10-08 Created: 2009-09-30 Last updated: 2009-10-01Bibliographically approved

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