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DEVELOPMENT OF NORMAL HUMAN COLON CELL CULTURES TO IDENTIFY UNREGULATED DISINFECTION BY-PRODUCTS (DBPS) WITH CARCINOGENIC POTENTIAL.
Citation:
JONES, C., S. Y. THAI, W. O. WARD, M. MOYER, AND A. B. DEANGELO. DEVELOPMENT OF NORMAL HUMAN COLON CELL CULTURES TO IDENTIFY UNREGULATED DISINFECTION BY-PRODUCTS (DBPS) WITH CARCINOGENIC POTENTIAL. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
We are developing an in vitro system to identify DBPs with a potential to transform normal human colonocytes (NCM460 cells) into malignant cells.
Description:
Epidemiological studies have linked the consumption of chlorinated surface waters to an increased risk of colorectal cancer. Approximately 600 DBPs, less than half of the total organic carbon in drinking water have been identified. We are developing an in vitro system to identify DBPs with a potential to transform normal human colonocytes (NCM460 cells) into malignant cells. Halonitromethanes (HNMs) were selected and compared to DBPs demonstrated to induce colon cancer in laboratory animals. NCM460 cultures were characterized for cytotoxicity and genotoxicity induced by several classes of DBPs. The order of toxicities was HNMs>HAAs>THMs. Within a DBP series, the toxicity increased with the degree of bromination and decreased with the molecular weight. For cell transformation studies NCM460 cells were exposed to a non-cytotoxic concentration of azoxymethane (colon carcinogen), bromochloroacetic acid, tribromomethane, dibromonitromethane or tribromonitromethane for 3 - 10 days. Cells growing in suspension from all chemical treatments when subcultured formed colonies in soft agar (untreated cells did not), a characteristic of transformation. Microarray analyses were performed on NCM460 cells following treatment with the test chemicals. Early data showed that the Wnt signaling pathway and cell-cell adherens junctions were upregulated for all chemical treatments. These data suggest that while no toxicity data are available for the halonitromethanes, they may pose a carcinogenic risk since they share activation of pathways characteristic of the colon carcinogens. Proof of this would be obtained if the malignancy of the transformed cells is demonstrated in immunocompromised mice. This system would then prove useful in identifying priority, unregulated DBPs for carcinogenesis.