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EARLY GENE EXPRESSION CHANGES IN THE LIVERS OF MICE EXPOSED TO DICHOLORACETC ACID
Thai, S. F., J W. Allen, A B. DeAngelo, M H. George, AND J C. Fuscoe. EARLY GENE EXPRESSION CHANGES IN THE LIVERS OF MICE EXPOSED TO DICHOLORACETC ACID. Presented at American Association for Cancer Research, San Francisco, CA, April 6-10, 2002.
EARLY GENE EXPRESSION CHANGES IN THE LIVERS OF MICE EXPOSED TO DICHLOROACETIC ACID
Dichloroacetic acid COCA) is a major by-product ofwater disinfection by cWorination. Several
studies have shown that DCA induces liver tumors in rodents when administered in drinkmg water . The mechanism of DCA carcinogenicity is not clear, and we speculate that changes in gene expression may be important. We used a cDNA micro array method to analyze changes in gene expression induced by DCA treatment. 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 Mouse 1.2 cDNA arrays and Atlas Stressrroxicology arrays were purchased from Clontech, and Atlaslrnage 1.5 was used to analyze the data. From replicate experiments, we detected several genes with 2- to 5-fold suppression of expression in the livers ofDCA-treated mice. From Atlas 1.2 cDNA arrays, 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-l, angiogenin and prothrombin precursor. From Atlas Stress/Toxicology arrays, the suppressed genes were cytochrome P450 3All and liver carboxylesterase. Previously, we demonstrated by differential display analysis that AA T - 2 and liver carboxylesterase were suppressed by DCA. We did not detect any significantly induced gene expression by DCA, which is consistent with our earlier results ftom differential display analysis where most of the differentially expressed genes were suppressed by DCA. The levels of suppression of GST Pi-l , angiogenin, plasminogen precursor, prothrombin precursor, cytochrome P450 3All were confirmed by Northern analysis. However, the levels of expression ofvitronectin precursor, cathepsin D, and integrin alpha 3 precursor showed little difference between RNA ftom control and DCA-treated mouse livers by Northern analysis. Plasminogen is believed to playa role 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. Thrombin is generated ftom its precursor prothrombin and is involved in chemotaxis, proliferatien and extracellular matrix turnover. Angiogenin is a potent inducer of blood vessel formation. The Pi class of GST is the most ubiquitous of the GST family and can protect cells ftom carcinogenic chemicals. In conclusion, we have found that DCA suppresses the expression of three genes
involved in xenobiotic drug metabolism, i.e., GST Pi, liver carboxylesterase and cytochrome P450 3All. We also found that DCA suppresses the expression of four genes that are involved in tissue remodeling (AA T -2, angiogenin, prothrombin precursor and plasminogen precursor). Although it requires at least one year for DCA-induced liver tumors to become detectable, genes that are involved in tissue remodeling processes are affected by DCA as early as four weeks into treatment. We are currently analyzing the expression levels for these genes in later stages of DCA treatment as well as in DCA-induced liver tumors.
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Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL CARCINOGENESIS DIVISION
MOLECULAR TOXICOLOGY BRANCH