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CARCINOGENESIS: Mouse lung tumors exhibit specific Ki-ras mutations following transplacental exposure to 3-methylcholanthrene
1Departments of Pathology, University of Tennessee College of Veterinary Medicine Knoxville, TN 37901
2Departments of Compardtive Medicine, University of Tennessee College of Veterinary Medicine Knoxville, TN 37901
3Department of Pathology, University of Tennessee Medical Center Knoxville, TN 37901
4Departments of Cancer Biology and Physiology and Pharmacology, Bowman Gray School of Medicine, Medical Center Blvd. Winston-Salem, NC 27157, USA
4To whom correspondence should be addressed
A pharmacogenetic mouse model was utilized to determine the role of Cyplal expression on the formation of Ki-ras mutations in lung tumors following transplacental exposure to polycyclic aromatic hydrocarbons (PAHs). A backcross between Ah responsive male B6D2F1 mice and non-responsive female DBA mice resulted in a litter in which both responsive and nonresponsive fetuses resided in the same nonresponsive maternal environment Pregnant mothers received a single i.p. injection of either 10 or 30 mg/kg of 3-methylcholanthrene (MC) or olive oil vehicle on day 17 of gestation. At the higher dose of MC, the responsive offspring of both sexes had significantly (P < 0.05) higher incidences of lung tumors than their nonresponsive littermates. The male responsive mice also exhibited a significantly increased liver tumor incidence over the nonresponsive mice at the P / 0.05 level. Administration of 10 mg/kg of MC caused a very low incidence of lung tumors and did not result in the appearance of macroscopically visible liver tumors. Exons 1 and 2 of the Ki-ras gene were amplified from paraffin-embedded tissue samples. The PCR products were screened by allele-specific oligonucleotide hybridization (ASO). Thirteen of 16 lung tumors (81%) screened exhibited point mutations in the 12th or 13th codon, including seven tumors that contained GGT
GTT (GLY12VAL12) transversions, four which exhibited GGTTGT (GLY12CYS12) transversions, and two which contained GGCCGC (GLY13 ARG13) transversions. None of the tumors had mutations at codon 61. The results obtained by ASO were confirmed by cloning and sequence analysis of the PCR products from four of these tumors. Within the subset of 16 tumors examined in this study, the same types of mutations in the Ki-rasgene were generally present in both responsive and nonresponsive mice, although GC transversions were found in two tumors from a single responsive female mouse. Interestingly, while both males and females exhibited the GGTGTT mutations at codon 12, the GGTTGT transversion was only found in male mice. These results are consistent with a key role for Cyplal in modulating
individual susceptibility to cancer formation through the formation of reactive intermediates that bind to DNA and result in activating mutations in key regulatory molecules
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