Abstract
A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD‐1) mice to 0, 50, 100, 200, or 300 mg 3′‐azido‐3′‐deoxythymidine (AZT)/kg body weight (BW) daily for the duration of gestation (18–19 days) [National Toxicology Program,2006]. The incidence of alveolar/bronchiolar adenomas and carcinomas in the 200 and 300 mg/kg groups was significantly higher (P = 0.027 and 0.007, respectively) in male offspring, but not in females (P = 0.338 and 0.315, respectively). The purpose of the present study was to evaluate K‐ras mutation status in lung tumors from the female offspring in AZT exposed groups and to determine whether at the molecular level there were signature K‐ras mutations in lung tumors that were different from spontaneous tumors. K‐ras mutation was detected by cycle sequencing of polymerase chain reaction (PCR)‐amplified DNA, isolated from formalin‐fixed, paraffin‐embedded lung tumors. K‐ras mutations were detected in 17 of 28 (61%) lung tumors from the female offspring in AZT exposed groups. No K‐ras mutations were detected in the 8 tumors examined from the female control group. The predominant mutations were Codon 12 G→T transversions in the 50, 100, and 300 mg/kg groups, and Codon 12 G→C transversions in the 200 and 300 mg/kg groups. K‐ras Codon 12 G→T transversions (TGT mutations) may be induced by oxidative DNA damage and 8‐oxoguanine (8‐oxoG), while K‐ras Codon 12 G→C transversions (CGT mutations) may be due to further oxidative lesions of guanine and 8‐oxoG. Environ. Mol. Mutagen., 2008. Published 2008 Wiley‐Liss, Inc.