Carcinogenesis, Vol 19, 2037-2042, Copyright © 1998 by Oxford University Press
SD Dertinger, AE Silverstone and TA Gasiewicz
The role of aromatic hydrocarbon receptor (AhR)-mediated events on the
genotoxicity of mainstream cigarette smoke condensate was investigated. In
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 approximately 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 microg/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.
ARTICLES
Influence of aromatic hydrocarbon receptor-mediated events on the genotoxicity of cigarette smoke condensate
Environmental Health Science Center, Department of Environmental Medicine, University of Rochester School of Medicine, NY 14642, USA.
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