邻苯二甲酸二丁酯干预Fgfs信号通路致雄性仔鼠尿道下裂发生的分子机制研究

Expression of fibroblast growth factors(Fgfs)in genital tubercle(GT)of hypospadiac male rats with utero exposure to di-n-butyl phthalate (DBP)

目的:通过验证邻苯二甲酸二丁酯(DBP)孕期染毒所致尿道下裂雄性仔鼠生殖结节内成纤维细胞生长因子(Fgfs)及其受体(Fgfr)信号通路中关键基因的表达异常,探讨其在DBP生殖毒性过程中的作用机制。方法:孕鼠20只,随机分2组,在怀孕(GD)14～18天期间,每天分别灌胃给予大豆油、DBP750mg/kg,出生后第1天(PND1),统计仔鼠出生数、尿道下裂发生率,称量雄性仔鼠体重,肛门至生殖器距离(AGD);PND7,取尿道下裂雄性仔鼠生殖结节,用实时定量(real-time quantitative)RT-PCR方法检测生殖结节中Fgf8、Fgf10、Fgfr2的mRNA表达水平。结果:DBP染毒后导致新生仔鼠与正常组相比数量明显减少,雄性仔鼠体重明显下降、AGD明显缩短,雄性仔鼠尿道下裂的发生率为48.83%。同时,与对照组相比,DBP致尿道下裂雄性仔鼠生殖结节中Fgf8、Fgf10、Fgfr2的mRNA的表达水平明显下降。结论:DBP对母体有着明显的毒性作用,DBP干预了Fgfs信号通路中关键基因的表达,这可能是DBP导致生殖结节发育异常,引起尿道下裂的重要原因。

Objective：To evaluate expression of Fgfs in hypopspadiac male rats induced by maternal exposure to DBP. Methods： Twenty pregnant rats were randomly divided into 2 groups and given DBP by gastric intubation at a dose of 0,750 mg/kg from gestation day （GD）14 to GD18. On postnatal day （PND）1 ,live pups were counted and hypospadias of male pubs were examined. The anogenital distance （AGD）and body weight of male pubs were measured. On PND7,real-time quantitative RT-PCR was used to quantify mRNA expression of Fgf8,Fgf10 and Fgfr2 in GT of hypospadiac male rats. Results：The number of live pubs in the DBP treated group significantly decreased. The body weight and the AGD of hypospadiac male rats significantly decreased. Moreover, significantly decreased expression of Fgf8,Fgf10 and Fgfr2 were observed. Conclusion：The down-regnlation expression of Fgfs signaling molecules might lead to the occurrence of hypospadias induced by maternal exposure to DBP.