Transplacental induction of a specific mutation in fetal Ha-ras and its critical role in post-natal carcinogenesis.
Mouse skin tumors were produced after transplacental initiation [with 7,12-dimethylbenz(a)anthracene], only when the skin was treated post-natally with a tumor-promoting agent (12-O-tetradecanoyl phorbol 13-acetate). DNA analysis of tumors showed that all carcinomas analyzed contained a specific mutation (A to T transversion) at the 61st codon of c-Ha-ras. Fifty per cent of the papillomas analyzed also had this same mutation. The A to T transversion at the 61st codon of Ha-ras was heterozygous in all positive papillomas and carcinomas. No such mutation was found when benzo(a)pyrene was used as an initiating agent. These results indicate that fetal c-Ha-ras can be transplacentally activated through a specific point mutation by a carcinogen, but a cell harboring such a mutation may remain dormant until it encounters a tumor-promoting stimulus.
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D002277:Carcinoma / Q000139:chemically induced* / Q000235:genetics; D003043:Cocarcinogenesis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D051379:Mice; D009154:Mutation; D010212:Papilloma / Q000139:chemically induced* / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011519:Proto-Oncogenes / Q000187:drug effects*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000008:administration & dosage / Q000633:toxicity*
D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D016283:Proto-Oncogene Proteins p21(ras); D013755:Tetradecanoylphorbol Acetate