Di-n-butyl phthalate (DBP) reduces epithelial-mesenchymal transition via IP3R in hypospadias during maternal exposure.
Di-n-butyl phthalate (DBP) reduces epithelial-mesenchymal transition via IP3R in hypospadias during maternal exposure.
复制标题
邻苯二甲酸二正丁酯 (DBP) 在母体暴露期间通过 IP3R 减少尿道下裂中的上皮间质转化
DOI：
10.1016/j.ecoenv.2020.110201
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发表时间：
2020-02
影响因子：
6.8
通讯作者：
Jiang Jun-Tao
中科院分区：
文献类型：
--
作者：
Zhu Yi-Ping;Zhao Wei;Sun Wen-Lan;Zhao Sheng;Chen Min;Pan Lei;Zhou Zheng;Xia Shu-Jie;Jiang Jun-Tao
目的探讨邻苯二甲酸二丁酯(DBP)氧化应激对泌尿系统发育的影响。方法采用Affymetrix大鼠230 2.0芯片检测正常和DBP诱导的尿路下裂大鼠生殖器结节(GT)的基因表达。应用实时荧光定量聚合酶链式反应和Western Blot方法检测正常组和正常组大鼠肾小管上皮细胞间充质转化相关分子标志物E-钙粘蛋白、β-连环素、蜗牛、N-钙粘附素的表达水平。结果进一步证实了阵列的体外实验结果。用Fluo-3-AM检测DBP治疗前后尿路上皮细胞内钙离子浓度的变化。结果正常对照组和L诱导的尿道下裂大鼠GTmRNA表达谱显示，IP3R高表达，μ异常。与对照组相比，IP3R、E-钙粘蛋白和β-连环蛋白在蛋白和基因水平的表达均增强。而Snail和N-钙粘附素的表达水平下降。DBP处理后细胞内钙离子浓度明显升高。结论DBP通过其氧化应激作用影响GT的发生，使尿路上皮细胞内钙离子浓度显著升高，抑制EMT，阻断尿道沟的融合过程，导致尿道下裂的发生。本研究对DBP治疗尿路下裂的分子机制有了新的认识，并可能为该病的治疗提供新的策略。
ObjectiveThis study focused on the oxidative stress effect of di-n-butyl phthalate (DBP) on development of the urinary system.MethodsWe examined the mRNA expression of genital tubercle (GT) in control and DBP induced hypospadias group by Affymetrix Rat 230 2.0 Array. Real-time PCR and Western Blot were used to detect the protein and mRNA expression levels of inositol-1,4,5-triphate-receptor (IP3R) and epithelial-mesenchymal-transition (EMT)-related molecular markers, such as E-cadherin, β-Catenin, Snail, N-cadherin, in the GT of hypospadiac male rats and controls. The results of array were further confirmedin vitro. The changes of intracellular calcium concentration in urethral epithelial cells were detected by Fluo-3-AM before and after DBP treatment. The levels of reactive oxygen species (ROS) in urethral epithelial cells were measured by DCFH-DA with different concentrations of DBP (0, 1, 10, 100 μmol/L) treatment.ResultsThe mRNA expression profiles of GT in control and DBP induced hypospadias group showed high expression of IP3R and the abnormalities of EMT. Compared to the control group, the expression levels of IP3R, E-cadherin and β-Catenin increased at both the protein and mRNA levels. However the expression levels of Snail and N-cadherin decreased. The intracellular calcium concentration increased significantly after DBP treatment. The effect of DBP on urethral epithelial cells was linked to the generation of oxidative stress.ConclusionDBP can influence the development of GT through its oxidative stress effect, which significantly increases the concentration of calcium and inhibits EMT in urethral epithelial cells, and block the fusion process of urethral groove, causing the occurrence of hypospadias. This study provides a new understanding of DBP's molecular mechanisms on hypospadias and may lead to new treatment strategies for the disease.
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影响因子：
1.9
作者：
Erin M. Shih;J. Graham
通讯作者：
Erin M. Shih;J. Graham
影响因子：
10.4
作者：
Blount BC;Silva MJ;Caudill SP;Needham LL;Pirkle JL;Sampson EJ;Lucier GW;Jackson RJ;Brock JW
通讯作者：
Brock JW
影响因子：
1.9
作者：
Aly, Hamdy A. A.;Hassan, Memy H.;Osman, Abdel-Moneim M.
通讯作者：
Osman, Abdel-Moneim M.
影响因子：
0.6
作者：
Laszlo, Sagodi;Akos, Kiss;Laszlo, Barkai
通讯作者：
Laszlo, Barkai
钙和ROS：相互互动。
影响因子：
11.4
作者：
Görlach A;Bertram K;Hudecova S;Krizanova O
通讯作者：
Krizanova O