Teratogenic effects of Doxorubicin in rats at midgestation and at term

Doxorubicin (DOXO) is an anticancer drug widely used against leukaemias and solid tumours. Doxorubicin is teratogenic in laboratory species, as demonstrated by a number of in vivo and in vitro experiments. In our in vitro study, the endoderm of the primitive gut and the caudal mesenchymes have been the main target tissues, while oxidative stress has been excluded as a mechanism in Doxorubicin-related abnormalities. The aims of the present work are the confirmation of our previous in vitro results (obtained on rat embryos cultured from 9.5 to 11.5 d.p.c.) in an in vivo model (midgestation) and the comparison of the abnormalities observed in the embryos at midgestation with malformations observable at term of pregnancy. For this purpose, pregnant rats were i.p. treated on 9.5 and 10.5 d.p.c. with DOXO. Embryos were analysed on 11 d.p.c., while foetuses were externally and viscerally analysed on 20 d.p.c. (term of gestation). The data collected at midgestation confirm the specific embryotoxic effects (particularly to the primitive gut and the caudal mesenchyme) previously observed in vitro. The data collected at term show the endoderm derivatives (gastrointestinal apparatus and respiratory tract) as the primary target organs, supporting the idea that the teratogenic activity of Doxorubicin is mediated by specific toxic effects directed to the primitive gut.