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Early transcriptional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology. (Lennart Dencker)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology. (Lennart Dencker)
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(English)Manuscript (preprint) (Refereed)
Abstract [en]

Cell-based in vitro assays would potentially reduce animal testing in preclinical drugdevelopment. Mouse embryos exposed to the teratogenic drug valproic acid (VPA)in utero for 1.5, 3 or 6 h on gestational day 8 were analyzed using microarrays.Significant effects on gene expression were observed as early as 1.5 h, and 85 probeswere deregulated across all time points. To find transcriptional markers of VPAinduceddevelopmental toxicity, the in vivo data were compared to previous in vitrodata on embryonal carcinoma P19 cells exposed to VPA for 1.5, 6 or 24 h. Maximalconcordance between embryos and cells was at the 6-h time points, with 163 genesshowing similar deregulation. Developmentally important Gene Ontology terms, suchas “morphogenesis” and “tube development” were overrepresented among putativeVPA target genes. The genes Gja1, Hap1, Sall2, H1f0, Cyp26a1, Fgf15, Otx2, andLin7b emerged as candidate in vitro markers of potential VPA-induced teratogenicity.

Keyword [en]
Gene ontology; in vitro toxicology; microarray; mouse embryo; neural tube defects; teratogen; toxicogenomics; valproic acid
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-110148OAI: oai:DiVA.org:uu-110148DiVA: diva2:275579
Available from: 2009-11-06 Created: 2009-11-05 Last updated: 2010-01-14
In thesis
1. Pluripotent Stem Cells of Embryonic Origin: Applications in Developmental Toxicology
Open this publication in new window or tab >>Pluripotent Stem Cells of Embryonic Origin: Applications in Developmental Toxicology
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

General toxicity evaluation and risk assessment for human exposure is essential when developing new pharmaceuticals and chemicals. Developmental toxicology is an important part of this risk assessment which consumes large resources and many laboratory animals. The prediction of developmental toxicity could potentially be assessed in vitro using embryo-derived pluripotent stem cells for lead characterization and optimization.

This thesis explored the potential of short-time assays with pluripotent stem cells of embryonic origin using toxicogenomics. Three established pluripotent stem cell lines; P19 mouse embryonal carcinoma (EC) cells, R1 mouse embryonic stem (mES) cells, and SA002 human embryonic stem (hES) cells were used in the studies.

Valproic acid (VPA), an antiepileptic drug which can cause the neural tube defects spina bifida in human and exencephaly in mouse, was used together with microarrays to investigate the global transcriptional response in pluripotent stem cells using short-time exposures (1.5 - 24 h). In addition to VPA, three closely related VPA analogs were tested, one of which was not teratogenic in mice. These analogs also differed in their ability to inhibit histone deacetylase (HDAC) allowing this potential mechanism of VPA teratogenicity to be investigated. The results in EC cells indicated a large number of genes to be putative VPA targets, many of which are known to be involved in neural tube morphogenesis. When compared with data generated in mouse embryos, a number of genes emerged as candidate in vitro markers of VPA-induced teratogenicity. VPA and its teratogenic HDAC inhibiting analog induced major and often overlapping deregulation of genes in mES cells and hES cells. On the other hand, the two non-HDAC inhibiting analogs (one teratogenic and one not) had only minor effects on gene expression. This indicated that HDAC inhibition is likely to be the major mechanism of gene deregulation induced by VPA. In addition, a comparison between human and mouse ES cells revealed an overlap of deregulated genes as well as species specific deregulated genes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 116
Keyword
Embryonic stem cell, Microarray, Toxicogenomics, Valproic acid, Developmental toxicology, Teratogenicity, Neural tube defects, Histone deacetylase inhibitor, In vitro toxicology
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-109946 (URN)978-91-554-7660-1 (ISBN)
Public defence
2009-12-18, B21, BMC, Husargatan 3, Uppsala, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-11-27 Created: 2009-11-01 Last updated: 2011-05-11Bibliographically approved

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