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Induction of Abasic Sites by the Drinking-Water Mutagen MX in Salmonella TA100
KING, L. C., S. D. HESTER, S. H. WARREN, AND D. M. DEMARINI. Induction of Abasic Sites by the Drinking-Water Mutagen MX in Salmonella TA100. MUTATION RESEARCH. Elsevier Science Ltd, New York, NY, 180(3):340-343, (2009).
MX is the dominant mutagen in drinking water, and the type of DNA damage that it induces to produce its mutagenic activity in vitro has never been identified experimentally. Thus, given the ubiquitous exposure to this disinfection by-product, which is (a) the most potent disinfection by-product in rodent carcinogenicity studies, and (b) induces tumors at a more organ sites than any disinfection by-product, it seemed important to understand its mode of action for its potent in vitro mutagenic activity.
Mutagen X (MX) is a chlorinated furanone that accounts for more of the mutagenic activity of drinking water than any other disinfection by-product. It is one of the most potent base-substitution mutagens in the Salmonella (Ames) mutagenicity assay, producing primarily GC to TA mutations in TA100. MX does not produce stable DNA adducts in cellular or acellular DNA. However, theoretical calculations predict that it might induce abasic sites, which it does in supercoiled plasmid DNA but not in rodents. To investigate the ability of MX to induce abasic sites in cellular DNA, we used an aldehydic site assay to detect abasic sites in DNA from Salmonella TA100 cells treated for 1.5 h with MX. At 0, 2.3, and 4.6 microM, MX induced mutant frequencies (revertants/10(6) survivors) and percent survivals of 2 (100%), 14.9 (111%), and 59.3 (45%), respectively. The frequencies of abasic sites (sites/10(5) nucleotides) for the control and two concentrations were 5.9, 6.2, and 9.7, respectively, with the frequency at the highest concentration being significant (P<0.001). These results provide some evidence for the ability of MX to induce abasic sites in cellular DNA. However, the lack of a dose response makes it unclear whether this DNA damage underlies the mutagenic activity of MX.
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