title: Differential sensitivity to lung tumorigenesis following transplacental exposure of mice to polycyclic hydrocarbons, heterocyclic amines, and lung tumor promoters.
abstract: Research conducted by 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-methylcholanthrene (MC). In this review, we describe our more recent studies on the effects of MC and cotreatment with the lung tumor promoter, butylated hydroxytoluene (BHT), on lung tumor formation in the intermediately susceptible BALB/c strain of mice, and the determination of the potential carcinogenicity of the heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in resistant mouse strains. BALB/c mice showed a similar incidence of lung tumors, both in terms of percentage of mice with tumors and number of tumors per mouse, as found in the resistant [D2 x B6D2F1]F2 mice. Ki-ras point 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 demonstrated a similar association of Ki-ras mutations with tumor stage. Interestingly, 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% incidences observed in [D2 x B6D2F1]F2 mice. BHT had no statistically significant effect on tumor incidence, multiplicity, or Ki-ras mutational spectrum in BALB/c mice treated in utero with MC, although a trend toward increased tumor multiplicity was observed. Finally, experiments initiated to assess the transplacental 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 induction of Cyp1a1, Cyp1b1, or glutathione S-transferases (GSTs) in fetal lung and liver tissues observed. This implies that at least under these experimental conditions, IQ may not be an important transplacental carcinogen. Overall, these data demonstrate that mutagenic damage to Ki-ras is a critical early event mediating murine lung tumorigenesis in both sensitive and resistant strains. Strain-dependent differences in the Ki-ras mutational spectrum may be associated with their differential susceptibility to lung tumor initiation.
authors.affiliation: Departments of Cancer Biology and Physiology and Pharmacology Comprehensive Cancer Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1082, USA. msmiller@wfubmc.edu
authors.forename: M S
authors.initials: MS
authors.lastname: Miller
authors.forename: K M
authors.initials: KM
authors.lastname: Gressani
authors.forename: S
authors.initials: S
authors.lastname: Leone-Kabler
authors.forename: A J
authors.initials: AJ
authors.lastname: Townsend
authors.forename: A M
authors.initials: AM
authors.lastname: Malkinson
authors.forename: M G
authors.initials: MG
authors.lastname: O'Sullivan
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002084:Butylated Hydroxytoluene / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D065633:Cytochrome P-450 CYP1B1; D018450:Disease Progression; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000473:pathology; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D006912:Hydroxyquinolines / Q000378:metabolism / Q000633:toxicity; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D018811:Maternal Exposure; D008748:Methylcholanthrene / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017354:Point Mutation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013045:Species Specificity
chemical_list: D002273:Carcinogens; D006912:Hydroxyquinolines; C060373:2-amino-3-methylimidazo(4,5-f)-quinoline 5-sulfate ester; D002084:Butylated Hydroxytoluene; D008748:Methylcholanthrene; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1