Teratogenesis by retinoic acid analogs positively correlates with elevation of retinoic acid receptor-beta 2 mRNA levels in treated embryos.
Retinoic acid (RA) plays an important role during normal embryogenesis, however high doses of RA are teratogenic. Retinoic acid receptor-beta 2 (RAR-beta 2) mRNA and protein levels were previously demonstrated to undergo rapid elevation in susceptible tissues after treatment with teratogenic doses of RA. In this report we compared the effects of a number of retinoids, which represent a wide variety of chemical structures and which differ in their teratogenic potencies, on RAR-beta 2 mRNA levels in mouse embryos 6 hr after treatment. Retinoid treatments which result in a high incidence of limb defects elevated RAR-beta 2 mRNA levels similarly (10-14 fold in the limb buds, 4-8 fold in the head, and 2-4 fold in the remainder of the body). On the other hand, retinoid treatments which cause a low or no incidence of limb defects resulted in minor changes in RAR-beta 2 mRNA levels in each embryonic region. Therefore, a strong positive correlation was found between the elevation of RAR-beta 2 mRNA levels and the retinoids which produce limb defects. This provides further evidence that an elevation of RAR-beta 2 mRNA levels, and subsequently protein levels, is an important event involved in mediating the effects of RA during dysmorphogenesis.
Department of Anatomy and Developmental Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
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Jiang
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Gyda
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Harnish
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Chandraratna
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Soprano
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Kochhar
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Soprano
D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000633:toxicity; D004480:Ectromelia / Q000139:chemically induced / Q000196:embryology; D005231:Fatty Acids, Unsaturated / Q000633:toxicity; D005260:Female; D007536:Isomerism; D051379:Mice; D008813:Mice, Inbred ICR; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis*; D012176:Retinoids / Q000633:toxicity*; D014212:Tretinoin / Q000031:analogs & derivatives
D001565:Benzoates; D005231:Fatty Acids, Unsaturated; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C082925:retinoic acid receptor beta; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; C077135:Ro 13-6307