Gestation stage- and carcinogen-specific K-ras mutations in mouse lung tumors initiated transplacentally

Lung tumors initiated in fetal mice on gestation days 14-16 by N-nitrosoethylurea (ENU) are larger and more malignant than those caused later in gestation or postnatally, suggesting a unique sensitivity to oncogene activation during fetal development. Pregnant BALB/c mice were treated with ENU (0.5 mmol/kg) or urethane (1 mg/g) on gestation day 14, 16, or 18. Resulting lung tumors in offspring one year of age were analyzed for K-ras and c-raf mutations by SSCP. No raf mutations were found. After ENU, frequency of codon 12 mutations in K-ras was 7/25 (28%) after day 14 exposure, 3/15 (20%) after day 16, and 0/8 (0%) after day 18 (P = 0.1, time-dependent trend), whereas codon 61 A to T mutation frequencies were respectively 4/25 (16%), 4/15 (27%), and 6/8 (75%) (P = 0.006; P = 0.003, time-dependent trend). Urethane caused lung tumors mainly after exposure on gestation day 18, and these contained only the codon 61 mutation, with high frequency (10/11 tumors). These results provide evidence for a qualitative and quantitative change in susceptibility to K-ras activation during pulmonary ontogenesis, with codon 12 decreasing and codon 61 increasing in vulnerability with progressive maturation of the lung.

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