Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung

Abstract

Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic hydrocarbon, is the most potent carcinogen ever tested in mouse skin and rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction, tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in strain A/J mouse lung. Groups of mice received a single i.p. injection of 0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment, DNA adducts were measured at times between 1 and 28 days, while tumors were counted at 250 days and analyzed for the occurrence of point mutations in codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung induced six major and four minor DNA adducts. Maximal levels of adduction occurred between 5 and 10 days after injection followed by a gradual decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti- and syn-11,12-dihydroxy-13,14-epoxy- 11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed by cochromatography. The major adduct was identified as a product of the reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced significant numbers of lung adenomas in a dose-dependent manner, with the highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based on the administered dose, DB[a,l]P was more active than other environmental carcinogens including benzo[a]pyrene. As a function of time-integrated DNA adduct levels, DB[a,l]P induced lung adenomas with about the same potency as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar in carcinogenic potency to other PAHs in the strain A/J mouse lung model. Analysis of the Ki-ras mutation spectrum in DB[a,l]P-induced lung tumors revealed the predominant mutations to be G-->T transversions in the first base of codon 12, A-->G transitions in the second base of codon 12, and A-->T transversions in the second or third base of codon 61, concordant with the DNA adduct profile.

Hormesis in Carcinogenicity of Non-genotoxic Carcinogens

“…Examples of hormesis also include TCDD-mediated reduction in tumor incidence after exposure to low doses of radiation 20 or metals such as selenium 38 . U-shape responses were also observed for chemically induced pulmonary tumors [39][40][41] and testicular cancer 42 .…”

Polycyclic Aromatic Hydrocarbons and Azaaromatic Compounds

“…Dibenzo[a,l]pyrene was tested for carcinogenicity in studies of single and repeated dermal application to mice, as well as several initiation-promotion studies on mouse skin; all studies gave positive results (153-156, 244, 253-255). Dibenzo[a,l] pyrene also induced oral cavity tumors when applied dermally to the tongue of hamsters (256) and lung tumors in mice following intraperitoneal injection (106,257). In addition to lung tumors, dibenzo[a,l]pyrene induced hepatic tumors and a variety of tumors at other sites when administered intraperitoneally to newborn mice (157).…”

The role of polycyclic aromatic hydrocarbon–DNA adducts in inducing mutations in mouse skin

“…These adenomas carry a variety of K-ras mutations (44% carry codon 12 GGT to TGT/GTT/CGT mutations and 56% carry codon 61 CAA to CTA/CGA/CAT/CAC mutations) [115,116]. A correlation of these adenoma mutations with DB[a,l]P-induced stable adducts has been suggested [115,116]. To our knowledge, depurinating adduct formation by DB[a,l]P in the A/J mouse lung has not been studied.…”