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INDUCTION OF DNA STRAND BREAKS BY TRIHALOMETHANES IN PRIMARY HUMAN LUNG EPITHELIAL CELLS
Landi, S, A. Naccarati, M. K. Ross, N. M. Hanley, L. A. Dailey, R. B. Devlin, M. Vasquez, R A. Pegram, AND D M. DeMarini. INDUCTION OF DNA STRAND BREAKS BY TRIHALOMETHANES IN PRIMARY HUMAN LUNG EPITHELIAL CELLS. MUTATION RESEARCH 538(1-2):41-50, (2003).
Trihalomethanes (TEMs) are disinfection by-products and suspected human carcinogens present in chlorinated drinking water. Previous studies have shown that many THMs induce sister chromatid exchanges and DNA strand breaks in human peripheral blood lymphocytes in vitro. Exposure to THMs occurs through oral, dermal, or inhalation routes, with the lung being a target of exposure by the latter route, although not a target for rodent carcinogenicity. Thus, to examine the genotoxicity of THMs in this tissue, we used the comet assay to examine the DNA damaging ability of 5 THMs in primary human lung epithelial cells. Cells were collected by scraping the large airways of 4 volunteers with a cytology brush and then passaging the cells no more than 3 times in order to have sufficient numbers for the experiments. Cells were exposed for 3 h to IO-, 100-1 or 1000-uM CHC13 CHC12Br, CHCIBr2, or CHBr3; CH2C12 was also used as a model dihalomethane for comparison to the THMs. The compounds ranked as follows for DNA damaging ability: CHC12Br > CHBr3 > CHC13 ~ CH2C12; CHC1Br2 was negative. Considerable inter-individual variation was observed. For example, CHC13 was genotoxic in only 2 subjects, and the interaction between dose and donor was highly significant (P < 0.001). The same variation was observed for CHC12Br, which was positive only in the 2 subjects in which CHC13 was negative. This variation was not due to the GSTT1-1 genotype of the subjects. Although 2 subjects were GSTT1-1 +, and 2 were GSTT1-1, no cultured cells with a GSTT1-1 + genotype had detectable GSTT1-1 enzymatic activity nor did any frozen epithelial cells that had not been cultured. However, GSTT1-1 enzymatic activity was detected in fresh (neither frozen nor cultured) lung cells. These results show that freezing or culturing causes lung cells to lose GSTT1-1 activity and that factors other than GSTT1-1 activity play a role in the variable responses of these human cells to the genotoxicity of the halomethanes studied here.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL CARCINOGENESIS DIVISION
MOLECULAR TOXICOLOGY BRANCH