维甲酸对胎鼠骨骼致畸作用的研究
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摘要
维甲酸是动物体内维生素A的代谢中间产物,在脊椎动物生长发育,尤其是胚胎发育过程中有重要作用。研究了维甲酸在不同剂量及不同胚胎发育时间点对骨骼发育的影响,并通过检测Cyp26b1基因的表达水平初步探究了维甲酸致畸作用的机制。结果显示,维甲酸导致的骨骼致畸程度与剂量呈依赖关系;孕期内维甲酸暴露时间不同,致畸部位也不同;维甲酸能够引起胎鼠Cyp26b1基因的表达下降。维甲酸暴露可导致骨骼发育畸形,这一作用可能是通过Cyp26b1基因的表达变化引起的。
Retinoic acid is a metabolic intermediate of vitamin A in animals. It plays an important role in the growth and development of vertebrates, especially in embryonic development. In this study, the effects of retinoic acid on skeletal development at different doses and different embryonic time were studied. The expression level of Cyp26 b1 gene was further detected to explore the mechanism of teratogenicity. The results showed that the degree of teratogenicity of skeletons was dose-dependent, and the teratogenic sites of skeletons varied with exposure time. Retinoic acid could cause decrease of the expression level of Cyp26 b1 gene. Retinoic acid can lead to skeletal malformation, which may be caused by the expression changes of Cyp26 b1 gene.
Retinoic acid is a metabolic intermediate of vitamin A in animals. It plays an important role in the growth and development of vertebrates, especially in embryonic development. In this study, the effects of retinoic acid on skeletal development at different doses and different embryonic time were studied. The expression level of Cyp26 b1 gene was further detected to explore the mechanism of teratogenicity. The results showed that the degree of teratogenicity of skeletons was dose-dependent, and the teratogenic sites of skeletons varied with exposure time. Retinoic acid could cause decrease of the expression level of Cyp26 b1 gene. Retinoic acid can lead to skeletal malformation, which may be caused by the expression changes of Cyp26 b1 gene.
引文
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[15] Helen J,Dranse I,Arthur V,et al..Genetic deletion of Cyp26b1 negatively impacts limb skeletogenesis by inhibiting chondrogenesis[J].J.Cell Sci.,2011,124(16):2723-2734.
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[2] Niederreither K,Abu-Abed S,Schuhbaur B,et al..Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development[J].Nat.Genet.,2002,31(1):84-88.
[3] Napoli J L.Physiological insights into all-trans retinoic acid biosynthesis[J].Biochim.Biophys.Acta,2012,1821(1):152-167.
[4] Wan D C,Siedhoff M T,Kwan M D,et al..Refining retinoic acid stimulation for osteogenic differentiation of murine adipose-derived adult stromal cells [J].Tissue Eng.,2007,13(7):1623-1631.
[5] Cohlan S Q.Excessive intake of vitam A as a cause of congenital anom alies in the rat [J].Science,1953,117:535-536.
[6] 张孟之,柴艺汇,管连城,等.当归补血汤对维甲酸致大鼠骨质疏松模型CYP24A1和骨钙素表达的影响[J].中药药理与临床,2019,35(1):10-14.
[7] 沈晨曦,毕文娟.全反式维甲酸在成骨分化中作用的研究现状[J].口腔医学研究,2018,34(10):1038-1041.
[8] 沈晨曦,李米,李金源,等.全反式维甲酸与骨形态发生蛋白联合应用对不同细胞的骨钙素及成骨相关基因表达的影响[J/OL].解放军医学杂志,2019,http://kns.cnki.net/KCMS/detail/11.1056.r.20190418.0847.002.html.
[9] 陈默,苏丽莉,余永莉,等.维甲酸致小鼠畸形最佳剂量的探索[J].毒理学杂志,2014,28(3):223-227.
[10] 夏敏杰,缪建成,王玉柱,等.维甲酸致大鼠胚胎外观畸形的剂量探索[J].中国新药杂志,2018,27(15):34-38.
[11] 张宏,李啸红.大鼠骨骼双染标本的制作方法[J].重庆医学,2012,41(2):153-155.
[12] 赵荧,张栩胤.整体显示大鼠骨骼和软骨的复合染色法[J].解剖学报,2006,7(1):117-119.
[13] Zhao Q,Dobbs-McAuliffe B,Linney E.Expression of Cyp26b1 during zebrafish early development[J].Gene Expr.Patterns.,2005,5(3):363-369.
[14] 韩飞,刘智皓,吴风瑞,等.维甲酸和Cyp26基因家族与生殖细胞分化[J].细胞生物学杂志,2008,31(3):355-360.
[15] Helen J,Dranse I,Arthur V,et al..Genetic deletion of Cyp26b1 negatively impacts limb skeletogenesis by inhibiting chondrogenesis[J].J.Cell Sci.,2011,124(16):2723-2734.
[16] Xue J,Gu H,Liu D,et al..Mitochondrial dysfunction is implicated in retinoic acid-induced spina bifida aperta in rat fetuses[J].Int.J.Dev.Neurosci.,2018,68:39-44.
[17] Wiley M J.The pathogenesis of retinoic acid induced vertebral abnorm alities in golden Syrian ham ster fetuses [J].Teratology,1983,28:341-353.
[18] Kohga H,Obata K.Retinoic acid-induced neural tube defects with multiple canals in the chick:Imm unohistochemistry with monoclonal antibodies [J].Neurosci.Res.,1992,13(3):175-187.
[19] 梁天琦.FGF3在正常和腭裂BALB/c小鼠腭突发育过程中的表达变化及差异[D].山西晋中:山西医科大学,硕士学位论文,2018.
[20] Stevison F,Jing J,Triphathy S,et al..Role of retinoic acid-metabolizing cytochrome P450s,CYP26 in inflammation and cancer [J].Adv.Pharmacol.,2015(74):373-412.
[21] Thomas J C,Gregg D.Mechanisms of retinoic acid signal and its roles in organ and limb development [J].Nat.Rev.Mol.Cell Biol.,2015,16(2):110-134.