Pediatric and Developmental Pathology

, Volume 1, Issue 6, pp 503–512

Methotrexate-Resistant Form of Dihydrofolate Reductase Protects Transgenic Murine Embryos from Teratogenic Effects of Methotrexate

  • Cari  Sutton
  • R. Scott  McIvor
  • Micki  Vagt
  • Barbara  Doggett
  • Raj P.  Kapur

ABSTRACT

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.

Key words: ectrodactyly, malformation, vascular disruption, teratogen, frontonasal dysplasia, aminopterin, amethopterin 

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Copyright information

© Springer-Verlag New York Inc. 1998

Authors and Affiliations

  • Cari  Sutton
    • 1
  • R. Scott  McIvor
    • 2
  • Micki  Vagt
    • 2
  • Barbara  Doggett
    • 1
  • Raj P.  Kapur
    • 1
  1. 1.Department of Pathology, University of Washington, Seattle, WA 98195, USA US
  2. 2.Institute of Human Genetics and Department of Laboratory Medicine and Pathology, Box 206 UMHC, 420 Delaware Street S.E., University of Minnesota, Minneapolis, MN 55455, USA US

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