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ALTERED GENE EXPRESSION IN MOUSE LIVERS AFTER DICHLOROACETIC ACID EXPOSURE
Citation:
Thai, S. F., J W. Allen, A B. DeAngelo, M H. George, AND J C. Fuscoe. ALTERED GENE EXPRESSION IN MOUSE LIVERS AFTER DICHLOROACETIC ACID EXPOSURE. REVIEWS IN MUTATION RESEARCH 543(2):167-180, (2002).
Description:
Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated that DCA exhibits hepatocarcinogenic effects in rodents when administered in drinking water. The mechanism(s) involved in DCA induction of cancer are not clear; thus, the present work was aimed at identifying changes in gene expression which may indicate critical alterations/pathways involved in this chemical s carcinogenic activities. We used cDNA microarray methods for analyses of gene expression in livers of mice treated with DCA (2 g/l) in drinking water for four weeks. Total RNA samples obtained from livers of control and DCA-treated mice were evaluated for gene expression patterns with Clontech AtlasTM Mouse 1.2 cDNA and AtlasTM Mouse Stress/Toxicology arrays, and the data analyzed with AtlasImage 2.01 and one-way Anova in JMP4 software. From replicate experiments, we identified 24 genes with altered expression, of which 15 were confirmed by Northern blot analysis. Of the 15 genes, 14 revealed expression suppressed 2- to 5- fold; they included following: MHR 23A, cytochrome P450 (CYP) 2C29, CYP 3A11, serum paraoxonase/arylesterase 1 (PON 1), liver carboxylesterase, alpha-1 antitrypsin, ER p72, glutathione S-transferase (GST) Pi 1, angiogenin. vitronectin precursor, cathepsin D (CTSD), plasminogen precursor (contains angiostatin), prothrombin precursor and integrin alpha 3 precursor (ITGA 3). An additional gene, CYP 2A4, had a 2-fold elevation in expression. Further, in ancillary Northern analyses of total RNA isolated from DCA-induced hepatocellular carcinomas (from earlier reported studies of mice treated with 3.5 g/l DCA for 93 weeks), many of the same genes (eight of thirteen) noted above showed a similar alteration in expression. In summary, we have identified specific genes involved in the functional categories of cell growth,tissue remodeling, apoptosis, cancer progression and xenobiotic metabolism that have altered levels of expression following exposures to DCA. These findings serve to highlight new pathways in which to further probe DCA effects that may be critical to it s tumorigenic activity.