Assessment of the genotoxicity of the rat carcinogen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in rat liver epithelial cells in vitro.
3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a disinfection by-product in chlorinated drinking water, is a multisite carcinogen in rats. One main target organ is the liver. The mechanism of the tumorigenicity was evaluated by testing the genotoxicity of MX in rat liver epithelial cell line cells. In the studies, the single cell gel/Comet assay and the hypoxanthine phosphoribosyl transferase locus assay to 6-thioguanine resistance were used. MX induced a dose-related genotoxic response in the comet assay. The lowest effective concentration was 120 microM when the exposure was in medium plus supplements and 3.75 microM when the exposure was in phosphate-buffered salt solution. MX also increased the frequency of TG(r) mutants, when the cells were treated in phosphate-buffered salt solution, at a concentration range of 2.3-9.2 microM. The present results show for the first time that MX causes DNA damage and gene mutations in rat liver epithelial cells, the target cells of MX's tumorigenicity in rats. We have earlier shown that MX also inhibits gap junctional intercellular communication in the same cells. The genotoxic effects were induced starting at about 60 times higher concentration, in identical exposure conditions, compared with the lowest concentration of MX causing the tumor promoter effect.
Mäki-Paakkanen
J
J
Department of Environmental Health, National Public Health Institute, PO Box 95, FI-70701 Kuopio, Finland. jorma.maki-paakkanen@ktl.fi
Hakulinen
P
P
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects*; D005663:Furans / Q000633:toxicity*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D005663:Furans; D009153:Mutagens; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; D007041:Hypoxanthine Phosphoribosyltransferase