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Development of Normal Human Colon Cell Cultures to Identify Unregulated Disiinfection By-products (DBPs) with a Carcinogenic Potential - GEMS.

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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 Disiinfection By-products (DBPs) with a Carcinogenic Potential - GEMS. Presented at Genetics and Environmental Mutagenesis Society (GEMS), Research Triangle Park, NC, October 06, 2008.

Impact/Purpose:

Developed an in vitro system that identifies DBPs with a potential to transform normal human colonocytes (NCM460 cells) into malignant cells. Halonitromethanes (HNMs) were selected and compared to the trihalomethanes (THMs) and haloacetic acids (HAAs) using NCM460 cells.

Description:

Epidemiological studies have linked the consumption of chlorinated surface waters to an increased risk of colorectal cancer. Approximately 600 DBPs, less that half of the total organic carbon in drinking water, have been identified of which 50 unregulated DBPs have received the highest ranking for potential toxicity. We are in the process of 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 trihalomethanes (THMs) and haloacetic acids (HAAs), some of whose members were 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 (1E-06 M) azoxymethane, bromochloroacetic acid, tribromomethane, dibromonitro-methane and tribromonitromethane for 3–10 days. Cells growing in suspension from all chemical treatments when sub cultured formed colonies in soft agar (untreated cells did not), a characteristic of transformation. Microarray analyses performed on NCM460 cells following treatment with the test chemicals showed the up regulation of Wnt signaling pathway and cell-cell adherens gene expression for all chemical treatments. These data suggest that while no toxicity data are available for the HMNs, they may pose a carcinogenic risk since they activate 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 screening test species.

Record Details:

Record Type:DOCUMENT( PRESENTATION/ ABSTRACT)
Product Published Date:11/06/2008
Record Last Revised:01/27/2009
OMB Category:Other
Record ID: 199327