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 resemble vascular disruptions in their evolution and final outcome. Previous studies suggest that inhibition of dihydrofolate reductase is responsible 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 ameliorates methotrexate teratogenicity. However, expression of the transgene in maternal tissues had no significant protective effect. The results confirm the role of dihydrofolate reductase inhibition in the pathogenesis of methotrexate-induced birth defects and provide a foundation for future studies of targeted transgene expression in select embryonic or placental cell populations.
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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C
Sutton
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McIvor
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M
Vagt
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B
Doggett
R P
RP
Kapur
D000014:Abnormalities, Drug-Induced / Q000201:enzymology / Q000517:prevention & control*; D000818:Animals; D002452:Cell Count / Q000187:drug effects; D046508:Culture Techniques; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D005552:Forelimb / Q000002:abnormalities / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental; D006614:Hindlimb / Q000002:abnormalities / Q000187:drug effects; D018878:Limb Buds / Q000002:abnormalities / Q000166:cytology / Q000187:drug effects; D008297:Male; D008727:Methotrexate / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic / Q000002:abnormalities / Q000378:metabolism; D011247:Pregnancy; D013623:Tail / Q000002:abnormalities / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
D004791:Enzyme Inhibitors; D013723:Teratogens; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate