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CYCLOPENTA-FUSED POLYCYCLIC AROMATIC HYDROCARBONS IN STRAIN A/J MOUSE LUNG: DNA ADDUCTS, ONCOGENE MUTATIONS, & TUMORIGENESIS
Citation:
Ross, J A. CYCLOPENTA-FUSED POLYCYCLIC AROMATIC HYDROCARBONS IN STRAIN A/J MOUSE LUNG: DNA ADDUCTS, ONCOGENE MUTATIONS, & TUMORIGENESIS. 3rd Int'l Mouse Lung Tumorigenesis Symposium, Toledo, Ohio, June 17, 2000.
Description:
Cyclopenta-fused Polycyclic Aromatic Hydrocarbons in Strain AJJ Mouse Lung: DNA Adducts, Oncogene Mutations, and Tumorigenesis.
We have examined the relationships between DNA adducts, Ki-ras oncogene mutations, DNA adducts, and adenoma induction in the lungs of strain A/J mice following i.p. administration of two cyclopenta-fused polycyclic aromatic hydrocarbons (PAHs), aceanthrylene (ACE) and benz[l]aceanthrylene (B[l]A). 32p-postlabeling analyses revealed that both PAHs induced multiple DNA adducts at both deoxyguanosine and deoxyadenosine in mouse lung DNA, resulting from metabolic activation primarily at the cyclopenta ring in each molecule. Maximal adduction levels were attained at 1 to 3 days after injection for ACE, and at 3 to 5 days after injection for B[l]A. ACE and B[l]A each induced comparable amounts of DNA adducts at comparable doses, but B[l]A was much more efficient at inducing tumors. At 100 mg/kg, B[l]A induced 86.2 tumors/mouse whereas ACE induced only 3.44 tumors/mouse at 160 mg/kg. As a function of delivered dose, as measured by time-integrated DNA adduct levels in lung DNA, B[l]A was one of the most potent PAH we have examined in this system, whereas ACE was the least potent. DNA recovered from the tumors was analyzed for the presence of activating mutations in the Ki-ras oncogene. ACE induced mutations in both codons 12 and 61, the most frequently observed mutations being OOT to TOT and OOT to COT transversions in codon 12 and CAA to CTA transversions in codon 61. B[l]A induced mutations only in codon 12, primarily OOT to COT transversions. The COT mutation in codon 12 has previously been associated with other cyclopenta-fused PAH induced tumors in this system.
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