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Embryonic Mutation as a Possible Cause of in Utero Carcinogenesis in Mice Revealed by Postnatal Treatment with 12-O-Tetradecanoylphorbol-13-acetate¹

Department of Radiation Biology, Faculty of Medicine, Osaka University, Nakanoshima, Kita-ku, Osaka 530, Japan

Although in utero irradiation at early stages induced a high incidence of somatic mutations at coat color genes in the embryos of a specified tester strain (PT x HT F₁) of mice, it was not carcinogenic by itself. However, in utero-irradiated animals did develop skin tumors and hepatomas (but not leukemias) by the postnatal administration of 12-O-tetradecanoylphorbol-13-acetate. The incidence of both tumors and embryonic mutations increased with in utero doses of X-rays. Furthermore, a large reduction of tumor incidence, about 80%, was observed by low-dose-rate irradiation, similar to the 75% reduction in spot size found for embryonic mutations. The tumor nodule size was also dramatically reduced by low-dose-rate irradiation. Consequently, the induced incidence and size of tumors produced by 12-O-tetradecanoylphorbol-13-acetate treatment parallel those which are observed for coat color mutations as expected, because somatic mutations observed in the pigment cells must similarly occur in embryonic cells of other organs. The larger the clone of mutant cells, the greater their chance of becoming tumorigenic by 12-O-tetradecanoylphorbol-13-acetate posttreatment. These results strongly support the recent epidemiological survey showing that adult types of cancers, but not leukemias, are increasing in the atomic bomb survivors exposed in utero, since humans are continuously exposed to a variety of cancer-promoting agents in contrast to experimental animals reared without such exposures.

¹ Supported by the Japanese Ministry of Education, Science, and Culture; the Science and Technology Agency of Japan; and the Nissan Science Foundation. A part of the work was presented at the IARC Symposium on Prenatal and Multigeneration Carcinogenesis (1988) and at the Annual Meetings of the Japanese Radiation Research Society (1988) (30), and the American Association for Cancer Research (1989) (31).

² To whom requests for reprints should be addressed, at Department of Radiation Biology, Faculty of Medicine, Osaka University, 3-57, Nakanoshima 4-chome, Kita-ku, Osaka 530, Japan.

³ Recipient of the Upjohn Travel Award.

Received 6/19/89. Revised 12/ 5/89.