title: MX, a by-product of water chlorination, lacks in vivo genotoxicity in gpt delta mice but inhibits gap junctional intercellular communication in rat WB cells.
abstract: 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a by-product of water chlorination, is a potent bacterial mutagen and rat carcinogen. In the present study, the in vivo mutagenicity, cell proliferative activity, and carcinogenicity of MX were investigated in gpt delta mice. Groups of 5 male and female 7-week-old gpt delta C57BL/6J transgenic mice were given MX at doses of 0, 10, 30, or 100 ppm in their drinking water for 12 weeks, and then killed to assess in vivo mutagenicity using 6-thioguanine and Spi- selection, and cell proliferative activity using immunohistochemistry for proliferating cell nuclear antigen (PCNA). Further groups of 10 male and female gpt delta mice were given 0 or 100 ppm MX for 78 weeks, and a full necropsy with histopathological examination of all organs was conducted to detect neoplastic lesions. The 12-week MX treatment did not result in mutagenicity in the livers or lungs or cell proliferative activity in several organs of the mice, and the 78-week treatment did not cause carcinogenicity. Additional investigations were conducted to evaluate the potential of MX to inhibit gap junctional intercellular communication (GJIC) in rat liver epithelial cells (WB cells) by the scrape loading/dye transfer method. Inhibition of GJIC was detected within 2 hr with a noncytotoxic dose of MX (4 microg/ml), followed by partial restoration after 5 hr. A second phase of inhibition occurred after 10 hr and then the lowered level persisted for the 24 hr-incubation period. Dose-dependent inhibition was evident at both 2 hr and 24 hr, with much stronger effects at the former time. These findings indicate that MX is not mutagenic, mitogenic or carcinogenic in mice, and suggest that the compound exerts epigenetic actions leading to GJIC inhibition.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo 158-8501, Japan. nishikaw@nihs.go.jp
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nishikawa
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Kazushi
authors.initials: K
authors.lastname: Okazaki
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Son
authors.forename: Keita
authors.initials: K
authors.lastname: Kanki
authors.forename: Madoka
authors.initials: M
authors.lastname: Nakajima
authors.forename: Naohide
authors.initials: N
authors.lastname: Kinae
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: James E
authors.initials: JE
authors.lastname: Trosko
authors.forename: Tohru
authors.initials: T
authors.lastname: Inoue
authors.forename: Masao
authors.initials: M
authors.lastname: Hirose
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D002713:Chlorine / Q000737:chemistry; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D029968:Escherichia coli Proteins; D005260:Female; D005663:Furans / Q000633:toxicity*; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D010430:Pentosyltransferases; D011506:Proteins / Q000235:genetics; D051381:Rats; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D018508:Water Purification
chemical_list: D002273:Carcinogens; D029968:Escherichia coli Proteins; D005663:Furans; D009153:Mutagens; D011506:Proteins; D014874:Water Pollutants, Chemical; D002713:Chlorine; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; D010430:Pentosyltransferases; C071962:Gpt protein, E coli