Academic journal article Environmental Health Perspectives

Valproic Acid Teratogenicity: A Toxicogenomics Approach

Academic journal article Environmental Health Perspectives

Valproic Acid Teratogenicity: A Toxicogenomics Approach

Article excerpt

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. Key words: biomarker, embryocarcinoma, galectin-1, histone deacetylase, in vitro toxicology, metallothionein, microarray, mouse embryo, neural tube defect, Sp1, teratogen, valproic acid, vinculin.

**********

Exposure during pregnancy to pharmaceuticals and environmental chemicals remains a worldwide problem. Assessing risk for human developmental toxicity is a major obstacle in drug development, as it relies on data from animal experiments, with associated concordance problems. A common understanding of basal mechanisms of developmental toxicity could assist risk assessment, but such mechanisms have unfortunately remained elusive. How individual teratogenic agents induce early developmental errors, and how widely different teratogens induce apparently similar defects by common or distinct mechanisms are still largely unknown. Compared with most established adult organs, the mammalian embryo comprises a moving target of highly dynamic cell interactions. This inherent complexity impedes the mechanistic interpretation of a chemical insult and may ultimately preclude what appear as more desirable in vitro methods from completely replacing whole-animal experiments in developmental toxicology. Nevertheless, cell-based screening methods could be devised based on knowledge of molecular mechanisms, pathways, and biomarkers of toxicity.

Recently, toxicogenomics has emerged as an attractive approach to uncover critical molecular events altered by toxicants (Aardema and MacGregor 2002; Iannaccone 2001; Nuwaysir et al. 1999). Using microarrays and profiling techniques, investigators can determine how gene expression responses to toxic exposure are linked to toxic outcome (phenotypic anchoring) (Paules 2003) and identify molecular targets and biomarkers of chemically induced toxicity. However, few microarray studies so far have addressed developmental toxicity (Docterman and Smith 2002) or embryonic development (Ko 2001; Smith and Greenfield 2003). We predict that disruption of the hierarchies of signaling and gene regulatory networks that control embryonic development may underlie many cases of chemically induced birth defects. Teratogenic chemicals are therefore likely to affect downstream gene expression as a cause or consequence, or both, of their adverse developmental effects. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.