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mRNA Expression is a Relevant Tool to Identify Developmental Neurotoxicants Using an In Vitro Approach
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
In vitro methods unit.
In vitro methods unit.
Johns Hopkins University.
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2009 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 113, no 1, 95-115 p.Article in journal (Refereed) Published
Abstract [en]

So far, only a few industrial chemicals have been identified as developmental neurotoxicants. Because the current developmental neurotoxicity (DNT) guideline (Organisation for Economic Cooperation and Development TG 426) is based entirely on in vivo studies that are both time consuming and costly, there is a need to develop alternative in vitro methods for initial screening to prioritize chemicals for further DNT testing. In this study, gene expression at the mRNA level was evaluated to determine whether this could be a suitable endpoint to detect potential developmental neurotoxicants. Primary cultures of rat cerebellar granule cells (CGCs) were exposed to well known (developmental) neurotoxicants (methyl mercury chloride, lead chloride, valproic acid, and tri-methyl tin chloride) for different time periods. A significant downregulation of the mRNA level for the neuronal markers (NF- 68, NF-200, N-methyl D-aspartate glutamate receptor, and gamma amino butyric acid receptor) was observed after exposure to methyl mercury chloride, valproic acid, and tri-methyl tin chloride. Moreover, a significant increase of the neural precursor marker nestin mRNA was also observed. The mRNA expression of the astrocytic markers (glial fibrillary acidic protein [GFAP] and S100b) was unchanged. In contrast, exposure to lead chloride significantly decreased the mRNA level of the astrocytic marker GFAP, whereas the neuronal markers were less affected. These results suggest that gene expression could be used as a sensitive tool for the initial identification of DNT effects induced by different mechanisms of toxicity in both cell types (neuronal and glial) and at various stages of cell development and maturation.

Place, publisher, year, edition, pages
Oxford university press , 2009. Vol. 113, no 1, 95-115 p.
Keyword [en]
gene expressiondevelopmental neurotoxicityprimary cell culture
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:su:diva-30072DOI: 10.1093/toxsci/kfp175OAI: diva2:241175
Available from: 2009-10-01 Created: 2009-10-01 Last updated: 2010-12-22Bibliographically 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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