Congenital Anomalies Induced by Triamcinolone Acetonide in Murine Embryos

Abstract

Introduction: We have studied the morphogenesis of anorectal malformations in mice using retinoids. Several investigators have reported an interaction between glucocorticoids and retinoids. It was supposed that glucocorticoids had some effects on the morphogenesis of murine embryos similar to retinoids. Therefore, we investigated alterations in the morphogenesis of murine embryos after triamcinolone acetonide (TAC) administration. Material and Methods: TAC was administered in a single dose (15 mg/kg or 30 mg/kg body weight) to pregnant ICR‐SLC mice on embryonic day 7 (E7), 8, 9, and 10. They were sacrificed on E18, and fetuses were examined for internal and external malformations. Randomly chosen fetuses were embedded in paraffin for immunohistochemical staining of the glucocorticoid receptor (GR). Results: The groups given 15 mg/kg TAC had one peak in the incidence of cleft palate on E9 (100 %) and the groups given 30 mg/kg TAC showed a biphasic pattern in the incidence of cleft palate on E7 and E10. No other anomalies were found. GR expression was marked in the subepithelial layer of palatal processes in the treated specimens. Conclusion: The group given 15 mg/kg TAC on E9 provided a good model of cleft palate in ICR‐SLC mice, and cleft palate was probably induced by various factors including disturbance of the bone morphogenetic protein (BMP) signaling pathway, shown by GR overexpression.

Key words

triamcinolone acetonide - cleft palate - glucocorticoid receptor

References

• 1 Bitoh Y, Shimotake T, Kubota Y, Kimura O, Iwai N. Impaired distribution of retinoic acid receptors in the hindgut-tailgut region of murine embryos with anorectal malformations.  J Pediatr Surg. 2001;  36 377-380
• 2 Boden S D, McCuaig K, Hair G, Racine M, Titus L, Wozney J M, Nanes M S. Differential effects and glucocorticoid potentiation of bone morphogenetic protein action during rat osteoblast differentiation in vitro.  Endocrinology. 1996;  137 3401-3407
• 3 Brinkley L L, Morris-Wiman J. Effects of chlorcyclizine-induced glycosaminoglycan alterations on patterns of hyaluronate distribution during morphogenesis of the mouse secondary palate.  Development. 1987;  100 637-640
• 4 Furukawa S, Usuda K, Abe M, Ogawa I. Histopathological findings of cleft palate in rat embryos induced by triamcinolone acetonide.  J Vet Med Sci. 2004;  66 397-420
• 5 Hackney J F. A glucocorticoid receptor in fetal mouse: its relationship to cleft palate formation.  Teratology. 1980;  21 39-51
• 6 Jin J Z, Ding J. Analysis of cell migration, transdifferentiation and apotosis during mouse secondary palate fusion.  Development. 2006;  133 3341-3347
• 7 Kubota Y, Shimotake T, Iwai N. Congenital anomalies in mice induced by etretinate.  Eur J Pediatr Surg. 2000;  10 248-251
• 8 Kusanagi T. Sensitive stages and dose-response analyses of palatal slit and cleft palate in C57BL/6 mice treated with a glucocorticoid.  Teratology. 1984;  29 281-286
• 9 Liu S L, Erickson R P. Genetic differences among the A/J x C57BL/6J recombinant inbred mouse lines and their degree of association with glucocorticoid-induced cleft palate.  Genetics. 1986;  113 745-754
• 10 Liu W, Sun X, Braut A, Mishina Y, Behringer R R, Mina M, Martin J F. Distinct functions for BMP signaling in lip and palate fusion in mice.  Development. 2005;  132 1453-1461
• 11 Monzon R I, PaPres J J, Hudson L G. Regulation of involucrine gene expression by retinoic acid and glucocorticoids.  Cell Growth Differ. 1996;  7 1751-1759
• 12 Presland R B, Tomic-Canic M, Lewis S P, Dale B A. Regulation of human profilaggrin promoter activity in cultured epithelial cells by retinoic acid and glucocorticoids.  J Dermatol Sci. 2001;  27 192-205
• 13 Shenefelt R E. Morphogenesis of malformations in hamsters caused by retinoic acid: relation to dose and stage at treatment.  Teratology. 1972;  5 103-118
• 14 Silbermann M, Levitan S. Corticosteroid-induced mandibular growth retardation and palatal malformation in the ICR mouse fetus.  J Anat. 1979;  128 747-765
• 15 Subramaniam N, Campion J, Rafter I, Okret S. Cross-talk between glucocorticoid and retinoic acid signals involving glucocorticoid receptor interaction with the homoeodomain protein Pbx1.  Biochem J. 2003;  370 1087-1095
• 16 Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y. Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian.  Development. 2002;  129 4135-4146
• 17 Zimmerman E F, Andrew F, Kalter H. Glucocorticoid inhibition of RNA synthesis responsible for cleft palate in mice: a model.  Proc Nat Acad Sci. 1970;  67 779-785