METHOTREXATE-RESISTANT FORM OF DIHYDROFOLATE-REDUCTASE PROTECTS TRANSGENIC MURINE EMBRYOS FROM TERATOGENIC EFFECTS OF METHOTREXATE

Methotrexate, a potent inhibitor of: the ubiquitously expressed enzyme dihydrofolate reductase, induces limb and facial anomalies that resem ble vascular disruptions in their evolution and final outcome. Previou s studies suggest that inhibition of dihydrofolate reductase is respon sible for methotrexate-induced embryopathy, although specific sites of methotrexate activity have not been well defined. In this report, we show that constitutive expression of a methotrexate-resistant form of dihydrofolate reductase in transgenic embryos and their placentas amel iorates methotrexate teratogenicity. However, expression of the transg ene in maternal tissues had no significant protective effect. The resu lts confirm the role of dihydrofolate reductase inhibition in the path ogenesis of methotrexate-induced birth defects and provide a foundatio n for future studies of targeted transgene expression in select embryo nic or placental cell populations.