MECHANISTIC RELATIONSHIPS BETWEEN DNA-ADDUCTS, ONCOGENE MUTATIONS, AND LUNG TUMORIGENESIS IN STRAIN-A MICE

This paper describes a series of studies on the lung tumorigenic activ ities of polycyclic aromatic hydrocarbons (PAHs) in strain A/J mice, t heir ability to form PAH-DNA adducts in lung tissues, and their abilit y to mutate the Ki-ras oncogene in PAH-induced tumors. Seven PAHs were studied: cyclopenta[cd]pyrene ( CPP), benzo[a]pyrene (B[a]P), benzo[b ]fluoranthene (B[b]F), dibenz[a,h] anthracene (DBA), 5-methylchrysene (5MC), benz[j]aceanthrylene (B[j]A), and dibenzo[a,l]pyrene (DB[a,l]P) . The dose-response data for the PAHs revealed 100-fold differences in tumor potency based on dose, with the order of activity DB[a,l]P, DBd > B[j]A > 5MC > CPP > B[a]P > B[b]F. Large differences in tumor multi plicity were also observed between the PAHs. DNA adducts were measured by P-32-postlabeling techniques on DNA from lungs of mice treated wit h these PAH's. DB[a,l]P gave syn- and anti;fjord-region diol-epoxide a dducts of dAdo and dGuo; DBA gave both bay-region diol-epoxide-dGuo an d bisdihydrodiol-epoxide adducts; CPP gave cyclopenta-ring-dGuo adduct s; B[j]A gave a mixture of cyclopenta-ring-dGuo and -dAdo adducts; 5MC gave anti-bay-region diol-epoxide-dGuo adducts; B[a]P gave bay-region diol-epoxide-dGuo adducts; and B[b]F gave 5-hydroxy-B[b]F-diol-epoxid e-dGuo adducts. Ki-ras codon 12 and 61 mutation analysis of PAH induce d tumors was performed using PCR and dideoxy sequencing methods. DB[a, l]P gave both codon 12 and codon 61 mutations. High proportions of cod on 12 TGT mutations from B[a]P-, B[b]F- and 5MC-, induced tumors and C GT mutations from CPP- and B[j]A-induced tumors were observed. DBA pro duced no mutations in Ki-ras codons 12 or 61 by direct sequencing. The interrelationships between the tumorigenesis, DNA adduct, and oncogen e mutation data are discussed.