A novel hypothesis for thalidomide-induced limb teratogenesis: redox misregulation of the NF-kappaB pathway.
Several hypotheses have been proposed to explain the mechanisms of thalidomide teratogenesis, although none adequately accounts for the observed malformations and explains the basis for species specificity. Recent observations that thalidomide increases the production of free radicals and elicits oxidative stress, coupled with new insights into the redox regulation of nuclear transcription factors, lead to the suggestion that thalidomide may act through redox misregulation of the limb outgrowth pathways. Oxidative stress, as marked by glutathione depletion/oxidation and a shift in intracellular redox potential toward the positive, occurs preferentially in limbs of thalidomide-sensitive rabbits, but not in resistant rats. DNA binding of nuclear factor kappa-B (NF-kappaB), a redox-sensitive transcription factor and key regulator of limb outgrowth, was shown to be significantly attenuated in rabbit limb cells and could be restored following the addition of a free radical spin-trapping agent, phenyl N-tert-butyl nitrone. The inability of NF-kappaB to bind to its DNA promoter results in the failure of limb cells to express fibroblast growth factor (FGF)-10 and twist in the limb progress zone (PZ) mesenchyme, which in turn attenuates expression of FGF-8 in the apical ectodermal ridge (AER). Failure to establish an FGF-10/FGF-8 feedback loop between the PZ and AER results in the truncation of limb outgrowth. We hypothesize that species-selective alterations in redox microenvironment caused by free radical production from thalidomide results in attenuation of the NF-kappaB-mediated gene expression that is responsible for limb outgrowth.
Hansen
Jason M
JM
Harris
Craig
C
D000818:Animals; D004247:DNA / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D017403:In Situ Hybridization; D018878:Limb Buds / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D017880:Limb Deformities, Congenital / Q000139:chemically induced* / Q000196:embryology / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000502:physiology; D011817:Rabbits; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013045:Species Specificity; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*; D013792:Thalidomide / Q000378:metabolism / Q000633:toxicity*
D005609:Free Radicals; D016328:NF-kappa B; D013723:Teratogens; D013792:Thalidomide; D004247:DNA; D005978:Glutathione