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Antisense Evidence for Nuclear Factor-B–Dependent Embryopathies Initiated by Phenytoin-Enhanced Oxidative Stress

Faculty of Pharmacy (J.C.K., P.G.W.) and Department of Pharmacology (P.G.W.), University of Toronto, Toronto, Ontario, Canada; and Unite de Biologie Moleculaire de l'Expression Genique, Unité de Recherche Associée 2582 Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France (S.M.)

Endogenous and xenobiotic-enhanced oxidative stress may initiate embryonic death and birth defects via reactive oxygen species (ROS) signaling pathways involving nuclear transcription factor-B (NF-B). Using embryo culture and a transgenic mouse engineered with a NF-B–dependent -galactosidase reporter gene, we employed NF-B antisense oligonucleotide therapy to determine whether NF-B signaling contributes to the embryopathic effects of the ROS-initiating teratogen phenytoin. Phenytoin selectively increased NF-B activity in target tissues and caused embryopathies, both of which were blocked by NF-B antisense oligonucleotides but not by sense and nonsense oligonucleotide controls. NF-B signaling may therefore contribute to the mechanism of ROS-mediated embryopathies.

Address correspondence to: Peter G. Wells, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2. E-mail: pg.wells{at}utoronto.ca

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