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MICROARRAY ANALYSIS OF DICHLOROACETIC ACID-INDUCED CHANGES IN GENE EXPRESSION
Citation:
Thai, S. F., J W. Allen, A B. DeAngelo, M H. George, AND J Fuscoe. MICROARRAY ANALYSIS OF DICHLOROACETIC ACID-INDUCED CHANGES IN GENE EXPRESSION. Presented at Annual American Association for Cancer Research, New Orlean, LA, March 24-28, 2001.
Description:
MICROARRAY ANALYSIS OF DICHLOROACETIC ACID-INDUCED CHANGES IN GENE EXPRESSION
Dichloroacetic acid (DCA) is a major by-product of water disinfection by chlorination. Several studies have demonstrated the hepatocarcinogenicity of DCA in rodents when administered in drinking water. The mechanism of DCA carcinogenicity is not clear and we speculate that changes in gene expression may be important. In order to analyze the changes in gene expression induced by DCA treatment, we used the cDNA micro array method. Mice were treated with DCA (2 g/l) in drinking water for four weeks. Total RNAs were obtained from livers of both control and DCA- treated mice for analysis. Atlas Mouse1.2 arrays were purchased from Clontech, and AtlasImage 1.5 was used to analyze the data. From replicate experiments, we found 7 genes whose expression was suppressed 2 to 5 fold in the livers of DCA-treated mice. We did not see any gene that was significantly induced by DCA which is consistent with our results from differential display analysis where most of the differentially expressed genes were suppressed by DCA. With microarray analysis, the suppressed genes were plasminogen precursor ( contains angiostatin), alpha-1 antitrypsinl-2 (AAT-2) precursor, cathepsin D (CTSD), integrin alpha 3 precursor, vitronectin precursor, glutathione S-transferase (GST) Pi-1, and prothrombin precursor. Previously we demonstrated by differential display analysis that AAT -2 was suppressed by DCA. Both integrin alpha 3 and vitronectin are involved in cell adhesion, and alpha 3 integrin has been shown to be involved in cell growth and tumor invasiveness. Plasminogen is believed to playa roll in the degradation of fibrin and various extracellular matrix proteins, taking part in physiological and pathological tissue remodeling processes including tumor invasion. Angiostatin, a potent endogenous inhibitor of angiogenesis, is generated by proteolysis of plasminogen by CTSD. The RNA levels for both plasminogen and the CTSD were suppressed in the livers of DCA-treated mice. This result is consistent with the fact that DCA induces tumor formation in mouse livers. Another function of CTSD is the mediation of IFN-gamma and TNF-alpha induced apoptosis. The decreased level of CTSD is consistent with published data that DCA suppresses apoptosis of hepatocytes in mice. Des-gamma- carboxyprothrombin, a derivative of prothrombin in the absence of Vitamin K, has been used as a tumor marker for hepatocellular carcinoma. The Pi class of GST is the most ubiquitous of the GST family and can protect cells from carcinogenic chemicals. In conclusion, we have found 7 genes involved in cell growth, cell differentiation, apoptosis and cancer formation that are affected by DCA.
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