A role for Drosophila in understanding drug-induced cytotoxicity and teratogenesis.

Drosophila research has been and continues to be an essential tool for many aspects of biological scientific research and has provided insight into numerous genetic, biochemical, and behavioral processes. As well, due to the remarkable conservation of gene function between Drosophila and humans, and the easy ability to manipulate these genes in a whole organism, Drosophila research has proven critical for studying human disease and the physiological response to chemical reagents. Methotrexate, a widely prescribed pharmaceutical which inhibits dihydrofolate reductase and therefore folate metabolism, is known to cause teratogenic effects in human fetuses. Recently, there has been resurgence in the use of methotrexate for inflammatory diseases and ectopic or unwanted pregnancies thus, increasing the need to fully understand the cytotoxicity of this pharmaceutical. Concerns have been raised over the ethics of studying teratogenic drugs like methotrexate in mammalian systems and thus, we have proposed a Drosophila model. We have shown that exposure of female Drosophila to methotrexate results in progeny with developmental abnormalities. We have also shown that methotrexate exposure changes the abundance of many fundamental cellular transcripts. Expression of a dihydrofolate reductase with a reduced affinity for methotrexate can not only prevent much of the abnormal transcript profile but the teratogenesis seen after drug treatment. In the future, such studies may generate useful tools for mammalian antifolate "rescue" therapies.