{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T07:50:08Z","timestamp":1767858608215,"version":"3.49.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2002,9,5]],"date-time":"2002-09-05T00:00:00Z","timestamp":1031184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Developmental Dynamics"],"published-print":{"date-parts":[[2002,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Thalidomide is known to induce oxidative stress, but mechanisms have not been described through which oxidative stress could contribute to thalidomide\u2010induced terata. Oxidative stress modulates intracellular glutathione (GSH) and redox status and can perturb redox\u2010sensitive processes, such as transcription factor activation and\/or binding. Nuclear factor\u2010kappa B (NF\u2010\u03baB), a redox\u2010sensitive transcription factor involved in limb outgrowth, may be modulated by thalidomide\u2010induced redox shifts. Thalidomide\u2010resistant Sprague\u2010Dawley rat embryos (gestation day [GD] 13) treated with thalidomide in utero showed no changes in GSH distribution in the limb but thalidomide\u2010sensitive New Zealand White rabbit embryos (GD 12) showed selective GSH depletion in the limb bud progress zone (PZ). NF\u2010\u03baB and regulatory genes that initiate and maintain limb outgrowth and development, such as <jats:italic>Twist<\/jats:italic> and <jats:italic>Fgf\u201010<\/jats:italic>, are selectively expressed in the PZ. Green fluorescent protein (GFP) reporter vectors containing NF\u2010\u03baB binding promoter sites were transfected into both rat and rabbit limb bud cells (LBCs). Treatment with thalidomide caused a preferential decrease in GFP expression in rabbit LBCs but not in rat LBCs. N\u2010acetylcysteine and \u03b1\u2010N\u2010t\u2010phenylbutyl nitrone (PBN), a free radical trapping agent, rescued GFP expression in thalidomide\u2010treated cultures compared with cultures that received thalidomide only. In situ hybridization showed a preferential decrease in <jats:italic>Twist<\/jats:italic>, <jats:italic>Fgf\u20108<\/jats:italic>, and <jats:italic>Fgf\u201010<\/jats:italic> expression after thalidomide treatment (400 mg\/kg per day) in rabbit embryos. Expression in rat embryos was not affected. Intravenous cotreatment with PBN and thalidomide (gavage) in rabbits restored normal patterns and localization of <jats:italic>Twist<\/jats:italic>, <jats:italic>Fgf\u20108<\/jats:italic>, and <jats:italic>Fgf\u201010<\/jats:italic> expression. These findings show that NF\u2010\u03baB binding is diminished due to selective thalidomide\u2010induced redox changes in the rabbit, resulting in the significant attenuation of expression of genes necessary for limb outgrowth. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/dvdy.10150","type":"journal-article","created":{"date-parts":[[2002,10,8]],"date-time":"2002-10-08T22:46:26Z","timestamp":1034117186000},"page":"186-194","source":"Crossref","is-referenced-by-count":66,"title":["Misregulation of gene expression in the redox\u2010sensitive NF\u2010\u03bab\u2010dependent limb outgrowth pathway by thalidomide"],"prefix":"10.1002","volume":"225","author":[{"given":"Jason 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