Differential sensitivity to lung tumorigenesis following transplacental exposure of mice to polycyclic hydrocarbons, heterocyclic amines, and lung tumor promoters

Research conducted bg this laboratory over the past decade has demonstrated the high susceptibility of the fetus to lung tumor formation following in utero exposure of the resistant C57BL/6 and DBA/2N strains of mice to 3-met hylcholanthrene (MC). In this review, we describe our more recent studies o n the effects of MC and cotreatment with the lung tumor promoter, butylated hydroxytoluene (BHT), on lung tumor formation in the intermediately suscep tible BALB/c strain of mice, and the determination of the potential carcino genicity of the heterocyclic amine, 2-amino-methylimidazo[4,5-f]quinoline ( IQ) in resistant mouse strains. BALB/c mice showed a similar incidence of l ung tumors, both in terms of percentage of mice with tumors and number of t umors per mouse, as found in the resistant [D2 x B6D2F1]F2 mice. Ki-ras poi nt mutations were found in 56% (20/36) of BALB/c lung lesions compared with an incidence of 79 % in [D2 x B6D2F1]F2 mice. BALB/c lung lesions demonstr ated a similar association of Ki-ras mutations with tumor stage. Interestin gly, a strain-dependent difference was observed in the mutational spectrum, where 62 % and 38% of the lesions in BALB/c mice exhibited G--> C and G--> T transversions, respectively, in contrast with the 16 % and 84 % incidenc es observed in [D2 x B6D2F1]F2 mice. BHT had no statistically significant e ffect on tumor incidence, multiplicity, or Ki-ras mutational spectrum in BA LB/c mice treated in utero with MC, although a trend toward increased tumor multiplicity was observed. Finally, experiments initiated to assess the tr ansplacental carcinogenicity of IQ in D2B6F1 mice demonstrated that 1 year after birth, no macroscopically or microscopically visible liver, lung, or colon tumors were found in the transplacentally treated offspring nor was i nduction of Cyp1a1, Cyp1b1, or glutathione S-transferases (GSTs) in fetal l ung and liver tissues observed. This implies that at least under these expe rimental conditions, IQ may not be an important transplacental carcinogen. Overall, these data demonstrate that mutagenic damage to Ki-ras is a critic al early event mediating murine lung tumorigenesis in both sensitive and re sistant strains. Strain-dependent differences in the Ki-ras mutational spec trum may be associated with their differential susceptibility to lung tumor initiation.