Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development

Eric Hill, David Nagel, John O'Neil, Liz Torr, Elizabeth Woehrling, Andrew Devitt, Mike Coleman

Research output: Contribution to journalArticle

Abstract

Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.
LanguageEnglish
Article numbere58822
Number of pages9
JournalPLoS ONE
Volume8
Issue number3
DOIs
Publication statusPublished - 19 Mar 2013

Fingerprint

valproic acid
neurodevelopment
lithium
Valproic Acid
Lithium
Gene expression
Genes
Gene Expression
gene expression
Gene Ontology
Intermediate Filaments
genes
cells
Cell Cycle
Cells
Down-Regulation
Cell Count
Pharmaceutical Preparations
drugs
Ontology

Bibliographical note

© 2013 Hill et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

  • toxicogenomics
  • gene ontology
  • stem cells
  • developmental neurotoxicity

Cite this

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title = "Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development",
abstract = "Mood stabilising drugs such as lithium (LiCl) and valproic acid (VPA) are the first line agents for treating conditions such as Bipolar disorder and Epilepsy. However, these drugs have potential developmental effects that are not fully understood. This study explores the use of a simple human neurosphere-based in vitro model to characterise the pharmacological and toxicological effects of LiCl and VPA using gene expression changes linked to phenotypic alterations in cells. Treatment with VPA and LiCl resulted in the differential expression of 331 and 164 genes respectively. In the subset of VPA targeted genes, 114 were downregulated whilst 217 genes were upregulated. In the subset of LiCl targeted genes, 73 were downregulated and 91 were upregulated. Gene ontology (GO) term enrichment analysis was used to highlight the most relevant GO terms associated with a given gene list following toxin exposure. In addition, in order to phenotypically anchor the gene expression data, changes in the heterogeneity of cell subtype populations and cell cycle phase were monitored using flow cytometry. Whilst LiCl exposure did not significantly alter the proportion of cells expressing markers for stem cells/undifferentiated cells (Oct4, SSEA4), neurons (Neurofilament M), astrocytes (GFAP) or cell cycle phase, the drug caused a 1.4-fold increase in total cell number. In contrast, exposure to VPA resulted in significant upregulation of Oct4, SSEA, Neurofilament M and GFAP with significant decreases in both G2/M phase cells and cell number. This neurosphere model might provide the basis of a human-based cellular approach for the regulatory exploration of developmental impact of potential toxic chemicals.",
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Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. / Hill, Eric; Nagel, David; O'Neil, John; Torr, Liz; Woehrling, Elizabeth; Devitt, Andrew; Coleman, Mike.

In: PLoS ONE, Vol. 8, No. 3, e58822, 19.03.2013.

Research output: Contribution to journalArticle

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T1 - Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development

AU - Hill, Eric

AU - Nagel, David

AU - O'Neil, John

AU - Torr, Liz

AU - Woehrling, Elizabeth

AU - Devitt, Andrew

AU - Coleman, Mike

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