Molecular mechanisms governing lung tumor pathogenesis in mice with differing susceptibility to polycyclic hydrocarbon-mediated tumorigenesis

Author

Lisa Lenore Wessner

Date of Award

8-1996

Degree Type

Thesis

Degree Name

Master of Science

Major

Life Sciences

Major Professor

Walter Farkas

Committee Members

Jill Sackman, Jay Joshi, Mark Miller

Abstract

A pharmacogenetic mouse model was utilized to determine the role of cytochrome P4501al expression on the formation of Ki-ra5 mutations in lung tumors following transplacental exposure to polycyclic aromatic hydrocarbons. A backcross between Ah responsive male B6D2F1 mice and nonresponsive 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 ip injection of either 10 or 30 mg/kg of 3- methylcholanthrene or olive oil vehicle on day 17 of gestation. At the higher dose of 3- methylcholanthrene, the responsive offspring of both sexes had significantly (P < 0.05) higher incidences of lung tumors than their nonresponsive litter mates. 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 3-methylcholanthrene 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 polymerase chain reaction products were screened by allele-specific hybridization. Thirteen of 16 lung tumors (81%) exhibited point mutations in the 12th or 13th codon, including 7 tumors that contained GGT-GTT (GLY¹²→VAL¹²) transversions, 4 which exhibited GGT-TGT (GLY¹²→CYS¹²) transversions, and 2 which contained GGC-CGC (GLY¹³→ARG¹³) transversions. None of the tumors had mutations at codon 61. These results are consistent with a key role for Cyp1a1 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.

Recommended Citation

Wessner, Lisa Lenore, "Molecular mechanisms governing lung tumor pathogenesis in mice with differing susceptibility to polycyclic hydrocarbon-mediated tumorigenesis. " Master's Thesis, University of Tennessee, 1996.
https://trace.tennessee.edu/utk_gradthes/10995