Similarity of the mechanism of chemical carcinogen-initiated teratogenesis and carcinogenesis in mice

Abstract

A maximum tolerated dose (15 mug/g) of the carcinogen 4-nitroquinoline 1-oxide (4NQO) induced neither fetal deaths nor malformations when given to pregnant ICR/Jcl mice at the sensitive stages (Days 9 to 11) for the induction of malformations, although these embryotoxicities were detected with urethan and X-ray. This may not be due to the lack of teratogenic actions of 4NQO, but to the difficulty this compound has in reaching the embryo, because direct injection of 4NQO into the amniotic cavity of the Day-11 embryo, so that exposure was more direct, induced a high incidence of malformations. Similarity of the mechanism of chemical carcinogen-initiated teratogenesis and carcinogenesis was also suggested by the following findings. Urethan-initiated teratogenesis was almost completely inhibited by posttreatment with caffeine during the period of 0 to 24 and 24 to 48 hr after urethan treatment, whereas it was not inhibited during the 48- to 72-hr post-urethan and the 6- to 30-hr pre-urethan period. The results are similar to those of 4NQO-initiated transformation in cultured mouse embryo cells and 4NQO- and urethan-initiated lung tumorigenesis in mice. Cells carrying preteratogenic or pretumorigenic damage produced by some chemical carcinogens may be extremely sensitive to caffeine treatment during and/or after the postcarcinogen DNA replication period, thus resulting in decrease of malformations and tumors. The process may be related to error-prone DNA repair, because caffeine is known to inhibit the postreplication repair in cultured mouse cells.