Differential teratogenesis of all-trans-retinoic acid administered on gestational day 9.5 to SWV and C57BL/6N mice: emphasis on limb dysmorphology.
Differential teratogenesis of all-trans-retinoic acid administered on gestational day 9.5 to SWV and C57BL/6N mice: emphasis on limb dysmorphology.
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妊娠第 9.5 天对 SWV 和 C57BL/6N 小鼠施用全反式视黄酸的差异致畸作用：强调肢体畸形。
DOI：
10.1002/bdra.20232
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
ScottJr,WJ
中科院分区：
文献类型：
--
作者：
Collins,MD;Eckhoff,C;Weiss,R;Resnick,E;Nau,H;ScottJr,WJ
背景：不同品系在畸形学反应方面的差异已有很好的文献记载。然而，由于维甲酸在许多物种中引起类似的畸形综合征，因此可以预测菌株差异很小。本研究的目的是描述和解释C57BL/6N和SWV小鼠品系在妊娠时全反式维甲酸(RA)诱发的导致后肢畸形的畸形效应的差异。方法用Wilson‘s切片和双染色技术分别确定内脏和骨骼畸形；根据体节计数进行发育分期；结果SC57BL/6N小鼠比SWV小鼠更易诱发胚胎死亡、心血管缺陷和前肢缺指，而对耳、胸腺、尾巴发育不全、腭裂、腹裂和肛门闭锁的诱导则相反。体节计数结果表明，有1个品系的杂交比亲本和正反交发育提前。在一些畸形的正反交之间，视黄醇的易感性是相等的，而对于另一些畸形，视黄醇的易感性则由母亲的基因决定。毒代动力学实验显示，全反式维甲酸的全胚胎峰值浓度在不同品系之间没有差异，但全反式维甲酸在C57BL/6N中的曲线下面积(AUC)是SWV胚胎的1.3倍。结论RA诱发的畸形谱具有菌株特异性，对前肢缺指的应变敏感性与所有已测试的致畸剂一致(即C57BL/6N比SWV更敏感)。不同品系的致畸效应不能用发育时间差异或全胚胎水平的毒物动力学差异来解释。出生缺陷研究(A部分)，2006。©2006 Wiley-Liss，Inc.
BACKGROUNDMouse strain differences in teratologic response are well documented. However, because retinoids cause similar malformation syndromes across many species, the strain differences may be predicted to be minimal. The goals of this study were to characterize and explain the differences between the C57BL/6N and SWV mouse strains in terms of all‐trans‐retinoic acid (RA)–induced teratologic effects at the time of gestation that cause postaxial forelimb ectrodactyly.METHODSVisceral and skeletal malformations were determined by Wilson's sectioning and double‐staining techniques, respectively; developmental staging was performed according to the somite count; and retinoid concentrations were assessed by HPLC.RESULTSC57BL/6N mice were more susceptible than SWV mice to induction of embryolethality, cardiovascular defects, and forelimb ectrodactyly, whereas the opposite was true for the induction of ear, thymus, and tail agenesis, and cleft palate, gastroschisis, and anal atresia. As determined by somite counts, 1 strain intercross was developmentally advanced compared to the parental strains and the reciprocal cross. Retinoid susceptibility was equivalent between the reciprocal crosses for some malformations and determined by the maternal genotype for others. Toxicokinetic experiments showed that whole‐embryo peak retinoid concentrations did not differ between the strains, but the area under the curve (AUC) for all‐trans‐RA was 1.3 times higher in C57BL/6N than in SWV embryos.CONCLUSIONSThe malformation spectrum induced by RA was strain‐specific, and the strain sensitivity for forelimb ectrodactyly was consistent with all previously tested teratogenic agents (i.e., C57BL/6N was more sensitive than SWV). The strain differences in teratologic effects were not explained by developmental timing differences or toxicokinetic differences at the whole‐embryo level. Birth Defects Research (Part A), 2006. © 2006 Wiley‐Liss, Inc.