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An Analysis of the Changing Urethan Response of the Developing Mouse Embryo in Relation to Mortality, Malformation, and Neoplasm¹

First Department of Surgery, Osaka University Medical School, Dôjima-hamadôri 3-12, Fukushima-ku, Osaka 553, Japan

Several different amounts of urethan (0.2 to 1.5 mg/g body weight) were given to pregnant mice on Days 3 to 19 of gestation, and a quantitative analysis of the changing urethan response of the developing mouse embryo in relation to mortality, growth inhibition, malformation, and neoplasm was investigated, utilizing the fast action and unrestricted placental penetration of urethan. When urethan was given before implantation on Day 3, preimplantation loss was observed. The treatment with urethan (1.5 mg/g) just after implantation on Day 7 caused complete resorption of the embryo. Early deaths were observed only when 1.5 mg/g were given on Day 8, and late deaths were observed on Days 8 to 11. Occurrence of malformation in an organ was confined to organs exposed at the very early stage of their organogenesis. Lung anomaly was induced at its maximum when 1.5 mg/g were given on Day 9, and liver anomaly peaked on Day 8. These stages corresponded to the time of differentiation of these fetal organs. The incidence of embryonic deaths and malformations by urethan showed a sharp threshold dose; it dropped from 93 to 34% at 1.5 mg urethan per g to virtually zero at 1.0 mg/g. This forms a striking contrast to the finding that tumors are induced in lung and liver when urethan is given during late organogenesis and fetal growth of each organ, even when very small amounts (0.2 mg) are given. Growth inhibition of fetal organs was observed when urethan was given during organogenesis and the early stage of fetal growth. The time of differentiation was most sensitive to small amounts of urethan (0.5 mg).

¹ This is Paper 5 of the series, "Transplacental Carcinogenesis by Urethan in Mice." This investigation was supported by a grant-in-aid for Cancer Research from the Japanese Ministry of Education.

Received 9/11/73. Accepted 5/10/74.