title: Genotoxic evaluation of chloroacetonitrile in murine marrow cells and effects on DNA damage repair gene expressions.
abstract: Although chloroacetonitrile (CAN), a disinfection by-product of chlorination of drinking water, is considered a rodent carcinogen that induces lung adenomas in mice, previous studies on its genotoxicity have yielded inconclusive results. Thus, its cancer mode of action has not been clearly defined. We evaluated CAN-induced genotoxicity in mice using mouse bone marrow micronucleus test, comet assays and expression of genes associated with DNA damage repair. Mice exposed to CAN at 8.75, 17.5, 35 and 52.5mg/kg for 7 days did not exhibit any significant increases in the incidence of micronuclei formation at 24 and 48h after last exposure. However, CAN caused significant suppressions of erythroblast proliferation at the highest dose. In the alkaline comet assay, there was a significant increase in the incidence of DNA strand breaks in mice killed after 3h of last treatment with 35 and 52.5mg/kg/day CAN, while no significant difference in the DNA strand breaks was found in mice killed after 24h of the last treatment. However, slight (but significant) CAN-induced oxidative DNA damage was detected following Fpg digestion at 3-h sampling time, digestion with EndoIII resulted in considerable increases in oxidative DNA damage at 3 and 24h after the last exposure to 35 and 52.5mg/kg/day CAN as detected by oxidative comet assays. The expression of DNA repair genes OGG1 , Apex1, PARP1 and p53 were up-regulated in mice given 35mg/kg/day CAN at 3h but not in 24h after the last treatment except OGG1 . However, the significant up-regulation of OGG1 at 24h after the last treatment further indicates the occurrence of oxidative DNA damage. Overall, CAN exposure is associated with up-regulation of DNA repair gene expression and the induction of oxidative DNA damage, which may be at least partially responsible for CAN-induced genotoxicity and eventually cause carcinogenicity.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: S M
authors.initials: SM
authors.lastname: Attia
authors.forename: S F
authors.initials: SF
authors.lastname: Ahmad
authors.forename: K M
authors.initials: KM
authors.lastname: Zoheir
authors.forename: S A
authors.initials: SA
authors.lastname: Bakheet
authors.forename: G K
authors.initials: GK
authors.lastname: Helal
authors.forename: A R
authors.initials: AR
authors.lastname: Abd-Allah
authors.forename: N O
authors.initials: NO
authors.lastname: Al-Harbi
authors.forename: K A
authors.initials: KA
authors.lastname: Al-Hosaini
authors.forename: O A
authors.initials: OA
authors.lastname: Al-Shabanah