Hyperglycaemia potentiates the teratogenicity of retinoic acid in diabetic pregnancy in mice
Hyperglycaemia potentiates the teratogenicity of retinoic acid in diabetic pregnancy in mice
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DOI：
10.1007/s00125-004-1350-6
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发表时间：
2004-03-01
期刊：
影响因子：
8.2
通讯作者：
Shum, ASW
中科院分区：
文献类型：
--
作者：
Leung, MBW;Choy, KW;Shum, ASW
目的/假设。我们最近在小鼠中发现，母体糖尿病增加了胚胎对维生素A代谢物视黄酸诱导的尾退化的易感性。在这里，我们测试是否在母体糖尿病环境中高血糖症是负责介导这种增加的易感性的关键因素。通过定期皮下注射葡萄糖使非糖尿病妊娠小鼠高血糖。相反，糖尿病妊娠小鼠用根皮苷处理以诱导肾性糖尿，从而降低血糖浓度。用视黄酸处理妊娠小鼠，并评估小鼠胚胎尾部退化的程度（根据尾长与顶臀长的比值进行测量）。同时检测胚胎Wnt-3a表达和细胞死亡情况。用葡萄糖处理的小鼠胚胎比盐水处理的对照组具有更大程度的由视黄酸诱导的尾部退化，Wnt-3a表达的下调增强，并且特别是在胚胎的尾部末端加剧了细胞死亡。用根皮苷处理的糖尿病小鼠胚胎与用维甲酸处理后的非糖尿病小鼠胚胎的尾部退化程度相似。高血糖症增加胚胎对维甲酸诱导的尾退化的易感性，其潜在的细胞和分子变化密切模仿母体糖尿病中发生的变化。降低糖尿病小鼠的血糖浓度完全消除了这种增加的对视黄酸的敏感性。这些结果表明，在母体糖尿病高血糖症是负责加强视黄酸的致畸作用的关键因素。
Aims/hypothesis. We recently showed in mice that maternal diabetes increases embryonic susceptibility to caudal regression induced by vitamin A metabolite retinoic acid. Here we tested whether in the maternal diabetic milieu hyperglycaemia is the critical factor responsible for mediating this increased susceptibility.Methods. Non-diabetic pregnant mice were made hyperglycaemic by subcutaneous injections of glucose at regular intervals. Conversely, diabetic pregnant mice were treated with phlorizin to induce renal glucosuria and thus reduce blood glucose concentrations. Pregnant mice were treated with retinoic acid and the extent of caudal regression in mouse embryos, measured in terms of the ratio of tail length to crown-rump length was assessed. Embryos were also examined for Wnt-3a expression and cell death.Results. Embryos of mice treated with glucose had a greater extent of caudal regression induced by retinoic acid than saline-treated controls, with enhanced down-regulation of Wnt-3a expression and exacerbated cell death specifically at the caudal end of the embryo. Embryos of diabetic mice treated with phlorizin had a similar extent of caudal regression to embryos of non-diabetic mice after treatment with retinoic acid.Conclusions/interpretation. Hyperglycaemia increases embryonic susceptibility to caudal regression induced by retinoic acid, with the underlying cellular and molecular changes closely mimicking those that occur in maternal diabetes. Reduction of blood glucose concentrations in diabetic mice completely abolishes this increased susceptibility to retinoic acid. These results suggest that in maternal diabetes hyperglycaemia is the critical factor responsible for potentiating the teratogenic effect of retinoic acid.