Organ variation in the mutagenicity of dimethylnitrosamine in Big Blue mice

Organ specificity in the lacI mutant frequency (MF) induced by dimethylnitrosamine (DMN) was analyzed in lung, liver, kidney, bone marrow, urinary bladder, and testis of Big Blue mice. Cell proliferative activity was also analyzed in some of these tissues by immunohistochemical staining of proliferating cell nuclear antigen (PCNA). Clastogenicity of DMN was concomitantly analyzed by the peripheral blood micronucleus assay with the same animals used for the lacI mutation assay. Five daily intraperitoneal (i.p.) treatments with DMN (1 mg/kg) increased MF in liver (6.2 x control), kidney (2.4 x control), and lung (2.1 x control). These are known target organs for DMN carcinogenesis. No MF increase was observed in nontarget organs studied, i.e., bone marrow, bladder, and testis. Single ip treatment with DMN also increased lacI MF in liver but the increases were smaller than in a 5-daily-treatment regimen. This result suggests that multiple dosing is more effective in the transgenic mutation assay. The enhancement of cell proliferation observed was in bronchial epithelia 7 days after treatment. No micronucleus induction in peripheral blood was observed 24 hours after 2 and 3 daily ip treatments with 1 mg/kg DMN. An increase in the incidence of micronucleated reticulocytes in peripheral blood was observed 48 hours after single ip treatment with 5 or 10 mg/kg DMN. The present study demonstrated organ-specific induction of gene mutations by DMN which suggests a relevance of this assay for the prediction of organ-specific carcinogenesis.