Tumorigenesis of carcinogenic environmental polycyclic aromatic hydrocarbons in strain A/J mice: Linkage to DNA adducts and mutations in oncogenes

Five polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), dibenz[a,h]anthracene (DBA), 5-methylchrysene (5MC), and cyclopenta[cd]pyrene (CPP) were examined for their lung tumorigenic activities in strain A/J mice, their ability to form DNA adducts in lung tissues, and their ability to mutate the Ki-ras oncogene in tumors. PAHs were administered by i.p. injection to male strain A/J mice and sacrificed after 8 months. The dose response data for each PAH was modeled to obtain potency values relative to B[a]P. DNA adducts were measured by P-32-postlabeling on DNA from lungs of mice treated with these PAHs, and all PAHs were found to adduct to guanine. Ki-ras codon 12 mutation analysis of PAH induced tumor DNA indicated high proportions of TGT mutations from B[a] P, B [b]F, and 5MC induced tumors and CGT mutations from CPP tumors. DBA produced no mutations in Ki-ras codon 12 above spontaneous levels. We conclude from the BNA adduct and Ki-ras mutation studies that bay region diol-epoxide-2'-deoxyguanosine PAH-DNA adducts are associated with the TGT mutations, and cyclopenta-ring oxide-2'-deoxyguanosine adducts are associated with the CGT mutations.