Susceptibility of C57BL/6 mice to tumorigenicity induced by dimethylnitrosamine and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the neonatal bioassay

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

“…Litters of mice were designated for saline or NDMA treatment at birth. A total dose of 10.5 mg/kg NDMA diluted in saline was administered intraperitoneally over two separate injections, according to (Dass et al, 1998). One-third of the dose (3.5 mg/kg NDMA in saline, 10 μL volume) was given at 8 days of age, and the remaining two-thirds of the dose (7 mg/kg, 20 μL volume) was given at 15 days of age.…”

“…We studied point mutations in livers from WT, Aag -/and AagTg mice exposed to 10.5 mg/kg NDMA, injected intraperitoneally in mice in a split dose at 8 (3.5 mg/kg) and 15 days old (7 mg/kg), a dosing regimen that was previously shown to cause liver and lung tumors in C57Bl6 mice (Dass et al, 1998) ( Figure S1). We extracted genomic DNA from livers 10 weeks after exposure, a timepoint at which there was no histological evidence of neoplastic changes ( Figure S2), thus reducing the possibility that mutations were caused by a tumor-associated mutator phenotype.…”

“…Here, we have turned our attention to an environmental contaminant that is a major public health concern, N -nitrosodimethylamine (NDMA). NDMA is potently genotoxic and carcinogenic in animals (Dass et al, 1999; Dass et al, 1998; Nishikawa et al, 1997; Peto et al, 1991; Vesselinovitch, 1969; Weghorst et al, 1989). Its genotoxicity is dependent upon metabolic activation by CYP2E1, which produces the highly reactive methyldiazonium ion (Haggerty and Holsapple, 1990; Lee et al, 1996; Sohn et al, 1991), which reacts with DNA to create 3MeA and other DNA lesions (Beranek, 1990; Pegg and Hui, 1978; Souliotis et al, 1998; Swenberg et al, 1991).…”

Relevance of Animal Carcinogenesis Findings to Human Cancer Predictions and Prevention

“…Outcomes of any study are influenced by multiple factors (e.g., experimental design, exposure levels, species, strain, sex, route of exposure, duration of exposure, metabolism, diet, and pathology) (Haseman, 1983;Schut et al, 1983;Gregory, 1988;Wolff et al, 1991;Griesemer and Eustis, 1994;Festing, 1995;Ginsberg et al, 1996;Dass et al, 1998;Keenan et al, 1999;Lovell et al, 1999). Although not perfect, there is enough concordance between human and rodent carcinogens, in repeatability of bioassay results, and in site-specificity to warrant continued use of existing hazard identification testing approaches until such time as we develop a more suitable means of identifying agents with human carcinogenic potential.…”

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

“…Here, we have turned our attention to an environmental contaminant that is a major public health concern, N-nitrosodimethylamine (NDMA). NDMA is potently genotoxic and carcinogenic in animals (Dass et al, 1998(Dass et al, , 1999Nishikawa et al, 1997;Peto et al, 1991;Vesselinovitch, 1969;Weghorst et al, 1989) and has been classified as an International Agency for Research on Cancer (IARC) group 2A probable human carcinogen (IARC, 2010). Its genotoxicity is dependent upon metabolic activation by CYP2E1, which produces the highly reactive methyldiazonium ion (Haggerty and Holsapple, 1990;Lee et al, 1996;Sohn et al, 1991), which reacts with DNA to create 3MeA, O 6 -methylguanine (O 6 MeG), and other DNA lesions (Swenberg et al, 1991;Pegg and Hui, 1978;Souliotis et al, 1998;Beranek, 1990).…”