Valproic Acid Teratogenicity: A Toxicogenomics Approach
| Autor: | Michael Stigson, Birger Scholz, Lennart Dencker, Kim Kultima, Anna-Maja Nyström, Anne-Lee Gustafson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: |
teratogen
Health Toxicology and Mutagenesis embryocarcinoma Cell Culture Techniques Apoptosis in vitro toxicology neural tube defect Toxicogenetics Histone Deacetylases Sp1 Embryonic and Fetal Development Mice In vivo valproic acid galectin-1 Animals Humans Neural Tube Defects Oligonucleotide Array Sequence Analysis mouse embryo Thyroid hormone receptor biology Microarray analysis techniques vinculin Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling Public Health Environmental and Occupational Health Articles Toxicogenomics metallothionein Molecular biology Cell biology Gene expression profiling Fatty acid synthase P19 cell histone deacetylase biology.protein biomarker lipids (amino acids peptides and proteins) Anticonvulsants Biological Assay Female Histone deacetylase microarray Biomarkers |
| Zdroj: | Environmental Health Perspectives |
| ISSN: | 1552-9924 0091-6765 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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