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ToxSci Advance Access published online on May 22, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm123
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Transgenic rescue of methotrexate-induced teratogenicity in Drosophila melanogaster

Joslynn G. Affleck and Virginia K. Walker

Department of Biology, Biosciences, room 2522, Queen's University, Kingston, Ontario, K7L 3N6, Canada

Corresponding Author: Virginia K. Walker; Department of Biology, Bioscience Complex, room 2521, Queen's University, Kingston, Ontario, K7L 3N6, Canada; tel: (613) 533-6000 ext. 77397; fax: (613) 533-6617; email: affleckj{at}biology.queensu.ca

Received April 6, 2007; revision received May 5, 2007; accepted May 7, 2007


  Abstract

The folic acid analog methotrexate (MTX), a competitive inhibitor of dihydrofolate reductase (DHFR), is used to treat a variety of cancers and auto-immune disorders. However, MTX also causes a wide range of toxic effects in healthy cells and is an established teratogen. Efforts to "rescue" the defects caused by MTX by administering a folate analog or by transgenic expression of a DHFR with an altered affinity for MTX have been attempted in a variety of mammals but limited protection was conferred. As a result, our understanding of the effect of MTX at the molecular genetic level remains incomplete and, in addition, continued mammalian sacrifice is not ideal. Due to the similarity of teratogenic effects produced by MTX in Drosophila melanogaster these insects were transformed with DHFR alleles to determine if rescue could be achieved. The resulting "MTX-resistant" flies were subsequently used to investigate changes in gene expression in response to MTX using qRT-PCR. The majority (12/14) of key transcripts that were affected in MTX-exposed females including transcripts involved in cell cycle, defense response and transport were "rescued" in the "MTX-resistant" transgenic flies. These studies illustrate the utility of this invertebrate model for the investigation of molecular effects of MTX-induced teratogenicity, MTX-resistant DHFRs for gene therapy techniques and teratogenic protection.

Key Words: methotrexate; dihydrofolate reductase; Drosophila melanogaster; teratogenesis; rescue; gene expression.


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