Influence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensate

The role of aromatic hydrocarbon receptor (AhR)-mediated events on the genotoxicity of mainstream cigarette smoke condensate was investigated. lit vitro studies with mouse hepatoma cells stably transfected with a DRE-dependent luciferase reporter indicate that cigarette smoke condensate is able to transform AhR to an active form which is capable of initiating gene transcription, Micronucleus formation in two hepatoma cell lines was used as an index of genotoxicity, Cigarette smoke condensate was observed to induce a higher frequency of micronuclei in Hepa1c1c7 cells relative to TAOc1BP(r)c1 cells, which express similar to 10-fold less AhR, Furthermore, the frequency of micronuclei was potentiated when Hepa1c1c7 cells were pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin, a high affinity ligand of AhR, These in vitro studies were followed by an in vivo experiment with Ahr(+/+) and Ahr(-/-) mice. Animals were dosed for three consecutive days with cigarette smoke condensate (0.5-10 mu g/kg/day, i.p. injection). The frequency of micronuclei in reticulocytes and total erythrocytes was determined in peripheral blood samples collected 24 h after the last administration. While condensate was found to increase the incidence of micronucleated reticulocytes in Ahr(+/+) mice, no increase was observed in the null allele animals. Furthermore, the frequency of micronucleated erythrocytes, a measure of basal chromosome-damaging activity, was slightly but significantly higher in Ahr(+/+) relative to Ahr(-/-) mice. Together, these data suggest that cigarette smoke contains chemicals which transform the AhR to an active transcription factor and AhR-regulated enzyme induction plays an important role in mediating the genotoxicity of this complex environmental pollutant.