Antisense evidence for nuclear factor-kappaB-dependent embryopathies initiated by phenytoin-enhanced oxidative stress.
Endogenous and xenobiotic-enhanced oxidative stress may initiate embryonic death and birth defects via reactive oxygen species (ROS) signaling pathways involving nuclear transcription factor-kappaB (NF-kappaB). Using embryo culture and a transgenic mouse engineered with a NF-kappaB-dependent beta-galactosidase reporter gene, we employed NF-kappaB antisense oligonucleotide therapy to determine whether NF-kappaB signaling contributes to the embryopathic effects of the ROS-initiating teratogen phenytoin. Phenytoin selectively increased NF-kappaB activity in target tissues and caused embryopathies, both of which were blocked by NF-kappaB antisense oligonucleotides but not by sense and nonsense oligonucleotide controls. NF-kappaB signaling may therefore contribute to the mechanism of ROS-mediated embryopathies.
Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2.
Julia C
JC
Kennedy
Sylvie
S
Memet
Peter G
PG
Wells
D000818:Animals; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010672:Phenytoin / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D017382:Reactive Oxygen Species; D010672:Phenytoin