Carcinogenic alterations in murine liver, lung, and uterine tumors induced by in utero exposure to ionizing radiation.
The atomic bombing of Hiroshima and Nagasaki and the nuclear accident at Chernobyl raised the question of prenatal sensitivity to ionizing radiation-induced cancer. In this study, mice were exposed to single doses of gamma-radiation (0.2-2.0 Gy) at different embryonic stages. The tumor incidence increased with dose from 15% in control mice to 35% in mice irradiated with 2.0 Gy on 18 d of prenatal life. Various oncogenic events were investigated in lymphoid, liver, lung, and uterine tumors. We observed threefold to fivefold increases in myc expression in 25% of the lymphomas, and the expression of Ha-ras and p53 genes decreased in 40% and 60% of the lung tumors by twofold to fivefold. Point mutations were tissue specific: Ha-ras codon 61 mutations were found in about 40% of the liver adenocarcinomas, Ki-ras codon 12 mutations in about 17% of lung tumors, and p53 mutations in about 15% of the lymphomas. Amplification and rearrangement of the p53, myc, and Ha-, Ki- and N-ras genes were not detected. Loss of heterozygosity on chromosome 4 at the multiple tumor suppressor 1 and 2 genes was observed in all types of malignancies. Allelic losses on chromosome 11 at the p53 locus were found in lymphoid, liver, and lung tumors, but they were absent from uterine tumors. Multiple oncogenic changes were often detected. The frequency of carcinogenic alterations was similar in spontaneous and radiation-induced lymphoid, liver, and uterine tumors. In radiation-induced lung adenocarcinomas, however, the incidences of many oncogenic changes were different from those found in their spontaneous counterparts. This suggests that different oncogenic pathways are activated during spontaneous and in utero gamma-radiation-induced murine lung carcinogenesis.
Lumniczky
K
K
Department of Molecular Radiobiology, National Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary.
Antal
S
S
Unger
E
E
Wunderlich
L
L
Hidvégi
E J
EJ
Sáfrány
G
G
D000818:Animals; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005720:Gamma Rays; D005784:Gene Amplification; D019942:Genes, p16; D016158:Genes, p53; D011905:Genes, ras; D008113:Liver Neoplasms / Q000196:embryology / Q000209:etiology*; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000196:embryology / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018895:Microsatellite Repeats; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D017354:Point Mutation; D011247:Pregnancy; D012334:RNA, Neoplasm / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics; D014594:Uterine Neoplasms / Q000196:embryology / Q000209:etiology*
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D011950:Receptors, Cholinergic