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Valproic acid teratogenicity: a toxicogenomics approach
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.
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.
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2004 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, Vol. 112, no 12, 1225-1235 p.Article in journal (Refereed) Published
Abstract [en]

Embryonic development is a highly coordinated set of processes that depend on hierarchies of signaling and gene regulatory networks, and the disruption of such networks may underlie many cases of chemically induced birth defects. The antiepileptic drug valproic acid (VPA) is a potent inducer of neural tube defects (NTDs) in human and mouse embryos. As with many other developmental toxicants however, the mechanism of VPA teratogenicity is unknown. Using microarray analysis, we compared the global gene expression responses to VPA in mouse embryos during the critical stages of teratogen action in vivo with those in cultured P19 embryocarcinoma cells in vitro. Among the identified VPA-responsive genes, some have been associated previously with NTDs or VPA effects [vinculin, metallothioneins 1 and 2 (Mt1, Mt2), keratin 1-18 (Krt1-18)], whereas others provide novel putative VPA targets, some of which are associated with processes relevant to neural tube formation and closure [transgelin 2 (Tagln2), thyroid hormone receptor interacting protein 6, galectin-1 (Lgals1), inhibitor of DNA binding 1 (Idb1), fatty acid synthase (Fasn), annexins A5 and A11 (Anxa5, Anxa11)], or with VPA effects or known molecular actions of VPA (Lgals1, Mt1, Mt2, Id1, Fasn, Anxa5, Anxa11, Krt1-18). A subset of genes with a transcriptional response to VPA that is similar in embryos and the cell model can be evaluated as potential biomarkers for VPA-induced teratogenicity that could be exploited directly in P19 cell-based in vitro assays. As several of the identified genes may be activated or repressed through a pathway of histone deacetylase (HDAC) inhibition and specificity protein 1 activation, our data support a role of HDAC as an important molecular target of VPA action in vivo.

Place, publisher, year, edition, pages
2004. Vol. 112, no 12, 1225-1235 p.
Keyword [en]
biomarker, embryocarcinoma, galectin-1, histone deacetylase, in vitro toxicology, metallothionein, microarray, mouse embryo, neural tube defect, Sp1, teratogen, valproic acid, vinculin
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-95977DOI: 10.1289/txg.7034.PubMedID: 15345369OAI: oai:DiVA.org:uu-95977DiVA: diva2:170377
Available from: 2007-05-15 Created: 2007-05-15 Last updated: 2009-10-09Bibliographically approved
In thesis
1. Transcriptomics and Proteomics Applied to Developmental Toxicology
Open this publication in new window or tab >>Transcriptomics and Proteomics Applied to Developmental Toxicology
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Developmental toxicology is an important part of preclinical drug toxicology as well as environmental toxicology. Assessing reproductive and developmental toxicity is especially expensive and time demanding, since at least two generations of animals are needed in the tests. In light of this there is a great need for alternative test methods in many areas of developmental toxicity testing.

The complete set of RNA transcripts in any given organism is called the transcriptome. Proteomics refers to the study of the proteins in a given organism or cell population. The work of this thesis has focused on the use of high throughput screening methods in transcriptomics and proteomics to search for molecular markers of developmental toxicity.

We have studied the global gene expression effects of the developmentally toxic substance valproic acid (VPA) using microarray technology. Several genes were found that display the same gene expression pattern in vivo using mouse embryos as the pattern seen in vitro using the embryocarcinoma cell line P19. Based on these observations, the gene Gja1 was suggested as one potential molecular marker of VPA induced developmental toxicity and potential marker of histone deacetylase (HDAC) inhibition in vitro.

Using 2D-DIGE technology, which measures relative protein abundances, the effect of neonatal exposure to the flame retardant PBDE-99 was studied in mouse brain (cortex, hippocampus and striatum) 24 hr after exposure. Differentially expressed proteins in the cortex and the striatum indicate that PBDE-99 may alter neurite outgrowth.

Finally, we have suggested several improvements in the use of the 2D-DIGE technology. Novel methods for normalizing data were presented, with several advantages compared to existing methods. We have presented a method named DEPPS that makes use of all identified proteins in a dataset to make comprehensive remarks about biological processes affected.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 58
Toxicology, 2D-DIGE, Valproic acid, PBDE-99, Flame retardant, Neural tube defects, Microarray, In vivo, In vitro, Biomarker, Brain growth spurt, Normalization, Mouse embryo, Toxicogenomics, Toxikologi
urn:nbn:se:uu:diva-7921 (URN)978-91-554-6914-6 (ISBN)
Public defence
2007-06-08, B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2007-05-15 Created: 2007-05-15Bibliographically approved

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