Carcinogenesis Advance Access originally published online on December 4, 2003
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Carcinogenesis, Vol. 25, No. 4, 637-643,
April 2004
Carcinogenesis vol.25 no.4 © Oxford University Press 2004; all rights reserved.
CARCINOGENESIS |
Mammary carcinogenesis and molecular analysis of in vivo cII gene mutations in the mammary tissue of female transgenic rats treated with the environmental pollutant 6-nitrochrysene
1 American Health Foundation Cancer Center, Institute for Cancer Prevention, Valhalla, NY 10595, USA, 2 Department of Basic Science, New York University Dental Center, New York, NY 10010, USA and 3 Department of Environmental Medicine, New York University, Medical Center, New York, NY 10016, USA
We determined the mutant fractions (MF) and mutational specificities in the cII gene in histologically confirmed normal, non-involved and tumor mammary tissues of female transgenic (Big Blue F344 x Sprague-Dawley)F1 rats treated with the environmental pollutant 6-nitrochrysene (6-NC). At 30 days of age, three groups were set up for oral treatment with 6-NC dissolved in trioctanoin, or trioctanoin alone once a week for 8 weeks. Two dose levels of 6-NC (100 and 200 µmol/rat) were selected on the basis of our previous carcinogenicity bioassays with CD rats. The rats were decapitated 32 weeks after the last carcinogen dose. Both incidence and multiplicity of mammary adenocarcinomas were significantly elevated in the high dose (36%, 0.57, P < 0.01) group but at the low dose these outcomes (16%, 0.23, P < 0.1) were not significantly different from those of control rats (3%, 0.03). The MF in normal, non-involved and tumor tissues from the mammary glands of 6-NC-treated rats were comparable. At the high and low doses, respectively (4.8 ± 2.0, 3.2 ± 2.1) the MF of 6-NC-treated rats, were significantly higher (P < 0.05) than that observed in control rats (1.2 ± 0.6). Control mutants consisted primarily of GC 
AT transitions, whereas 6-NC-induced mutants were comprised of several major classes of mutations with GC TA, GC CG, AT GC and AT TA as the most prevalent. Further studies indicated that the structures of 6-NC–DNA adducts in the mammary tissue are consistent with the mutational specificities. This is the first report that defines the relationship between carcinogenesis and mutagenesis, as well as between structures of 6-NC–DNA adducts and mutation characteristics in the target organ in vivo.
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