| 陈 敏,潘 磊,赵 圣,朱依萍,周 征,孙文兰,蒋君涛,董胜利.邻苯二甲酸二丁酯降低雄激素浓度导致尿道下裂发生机制研究[J].,2020,(4):629-633 |
| 邻苯二甲酸二丁酯降低雄激素浓度导致尿道下裂发生机制研究 |
| Reduced Androgen Level Induces Autophagy Leading Hypospadias Caused by Di-n-butyl Phthalate (DBP) |
| 投稿时间：2019-07-01 修订日期：2019-07-26 |
| DOI：10.13241/j.cnki.pmb.2020.04.006 |
| 中文关键词: 邻苯二甲酸二丁酯 尿道下裂 雄激素 自噬 |
| 英文关键词: Dibutyl phthalate Hypospadias Androgen Autophagy |
| 基金项目:国家自然科学基金项目（81771564）；上海浦江人才计划项目（17PJD033） |
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| 中文摘要: |
| 摘要 目的：验证邻苯二甲酸二丁酯（DBP）是通过降低血清雄激素水平导致自噬异常激活，同时探讨DBP致子代大鼠尿道下裂发生的具体机制。方法：将孕鼠随机分为DBP染毒组与对照组，并于妊娠期14-18天通过灌胃的方式，分别用DBP（750 mg/kg/天）饲养DBP染毒，用等量花生油饲养对照组。依照此方法成功构建了子代新生大鼠尿道下裂模型。采集子鼠生殖结节（GT）用福尔马林保存，用免疫组织化学（IHC）染色观察生殖结节组织中自噬水平，即LC3B及Beclin1表达水平；在子鼠麻醉后采集血液标本，用放射免疫分析方法观测子鼠血清睾酮水平。在原代大鼠尿路上皮细胞（PUECs）基础上，用Western印迹方法检测有无双氢睾酮（DHT）对PUECs中LC3I、LC3II及Beclin1表达水平影响。结果：DBP染毒组尿道下裂发生率为42.3%，对照组子代无尿道下裂。DBP染毒组子代GT组织中自噬表达较对照组明显增加。DBP染毒组（n=10）较对照组中血清睾酮水平有明显差异（n=10）（P＜0.05）。体外研究表明DHT缺乏组 Beclin1及LC3蛋白转化率水平较对照组升高。结论：孕期暴露于DBP可以诱发子代尿道下裂发生，这可能是由于DBP降低子鼠雄激素水平促使自噬发生导致的,然而该疾病的机制仍需要进一步研究。 |
| 英文摘要: |
| ABSTRACT Objective: To verify that reducing levels of serum androgen could induce abnormal activation of autophagy by di-n-butyl phthalate (DBP) during maternal exposure and further investigate the specific mechanism of DBP-induced hypospadias in male offspring. Methods: Pregnant rats were randomly divided into the DBP-treated group and the control group, the former were intragastrically treated with DBP at 750mg per kilogram of the body weight per day on the 14-18 days during gestation while the latter with the equivalent peanut oil. The hypothalamic model of the offspring newborn rats was successfully constructed according to the methods above. The expression level of autophagy markers, including LC3B and Beclin1, in the genital tubercle(GT) was measured by immunohistochemistry(IHC) staining after GT was harvested from male offspring and stored in Formalin. The level of serum testosterone in the rats were measured by radioimmunoassay with blood samples collected after anesthesia in offspring. The expression levels of LC3I, LC3II and Beclin1 were detected by Western blot in primary urethral epithelial cells(PUECs) under treatment with or without dihydrotestosterone. Results: The rate of hypospadias in the DBP-treated group was 42.3%, while no hypospadias was observed in the control group. The autophagy expression was increased apparently in GT tissues of DBP-treated groups while compared to the control group. The levels of serum testosterone in the DBP group (n=10) were significantly different from those in the control group (n=10)(P<0.05). In vitro studies, the Beclin1 and ratio of LC3II/LC3I in the DHT-deficient group were higher than those in the control group. Conclusion: Maternal Exposure to DBP can induce hypospadias, which may be due to DBP-induced autophagy by reducing serum androgen in offspring. However, the mechanism of this disease still needs further research. |
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