Maternal exposure to Di-n-butyl phthalate (DBP) aggravate gestational diabetes mellitus via FoxM1 suppression by pSTAT1 signalling
Maternal exposure to Di-n-butyl phthalate (DBP) aggravate gestational diabetes mellitus via FoxM1 suppression by pSTAT1 signalling
复制标题
母亲接触邻苯二甲酸二正丁酯 (DBP) 通过 pSTAT1 信号传导抑制 FoxM1 加重妊娠期糖尿病
DOI：
10.1016/j.ecoenv.2020.111154
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发表时间：
2020-12-01
影响因子：
6.8
通讯作者：
Jiang, Jun-Tao
中科院分区：
文献类型：
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作者：
Chen, Min;Zhao, Sheng;Jiang, Jun-Tao
该研究重点关注邻苯二甲酸二正丁酯（DBP）对磷酸化信号转导子和转录激活子1（pSTAT1）调节的叉头盒蛋白M1（FoxM1）表达的毒理学影响，这可能为妊娠期糖尿病（GDM）的发展提供新的认识，并为治疗提供潜在靶点。 STZ 组和 STZ + DBP 组在妊娠第 0 天（GD 0）通过腹腔注射将链脲佐菌素（STZ）（40 mg/kg）引入母鼠体内。 STZ + DBP 组在接下来的 3 天内通过口服喂养将 DBP 引入母鼠中（750 mg/kg/天）。 GD 1和GD 5检测大鼠空腹血糖水平的变化。GD 18测定母鼠和PIBC的胰岛素水平。GD 18进行口服葡萄糖耐量试验（OGTT）测试以检查GDM模型的稳定性。建立初级胰岛β细胞（PIBC）用于体外实验。我们通过免疫组织化学检查了胰腺中 FoxM1 和 pSTAT1 的表达。采用实时荧光定量PCR和Western blot检测PIBC中pSTAR1和FoxM1蛋白及mRNA基因表达水平。使用细胞计数试剂盒-8（CCK-8）和流式细胞术分析来测试细胞的活力和凋亡。结果显示，空腹测试和OGTT均显示STZ+DBP组的血糖水平高于其他组，胰岛素分泌水平低于其他组。 DBP 暴露后 FoxM1 显着受到抑制，而 pSTAT1 则高度表达。 FoxM1 可以受 pSTAT1 调节。 DBP可以通过其毒理作用影响GDM的进展，显着增加pSTAT1的表达并抑制FoxM1，导致β细胞活力下降。
The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet beta cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in beta cell viability.