Wu Ting-Shuan, Yang Jiann-Jou, Wang Yan-Wei, Yu Feng-Yih, Liu Biing-Hui
Graduate Institute of Toxicology , College of Medicine , National Taiwan University , Taipei , Taiwan . Email:
Department of Biomedical Sciences , Chung Shan Medical University , Taiwan . Email:
Toxicol Res (Camb). 2016 Jan 4;5(2):519-529. doi: 10.1039/c5tx00360a. eCollection 2016 Mar 1.
Mycotoxin ochratoxin A (OTA) frequently contaminates various food and feed products, including cereals, coffee and wine. While the nephrotoxicity and teratogenicity of OTA have been extensively documented, the molecular mechanisms associated with OTA toxicity remained poorly understood in a developing organism. We showed that zebrafish embryos exposed to OTA demonstrated incorrect heart looping and small heart chambers. OTA also impaired the renal morphology and reduced the glomerular filtration rate of the embryonic zebrafish. The treatment of embryos with OTA attenuated the expression of the prolactin receptor, a gene (PRLRa) that has a key role in organogenesis and osmoregulation in vertebrates. OTA not only inhibited the phosphorylation of STAT5 and AKT, but also down-regulated the level of serpina1 mRNA in a dose-dependent manner. On the other hand, the microRNA profiling based on RNA sequencing revealed the up-regulation of microRNA-731 (miR-731) in the OTA-treated embryos. Further analysis predicted that PRLRa was a target gene of miR-731. AntagomiR-731 restored PRLRa levels that had been reduced by OTA and also recovered the pronephros morphology that was damaged by OTA. These observations suggest that the exposure to OTA adversely affected the organogenesis of zebrafish, and the modulation of miR-731 and the PRLR signaling cascade contributed to the abnormal renal development mediated by OTA.
霉菌毒素赭曲霉毒素A（OTA）经常污染各种食品和饲料产品，包括谷物、咖啡和葡萄酒。虽然OTA的肾毒性和致畸性已有大量文献记载，但在发育中的生物体中，与OTA毒性相关的分子机制仍知之甚少。我们发现，暴露于OTA的斑马鱼胚胎出现心脏环化异常和心腔变小。OTA还损害了胚胎斑马鱼的肾脏形态，并降低了其肾小球滤过率。用OTA处理胚胎会减弱催乳素受体（一种在脊椎动物器官发生和渗透调节中起关键作用的基因，PRLRa）的表达。OTA不仅抑制STAT5和AKT的磷酸化，还以剂量依赖的方式下调serpina1 mRNA的水平。另一方面，基于RNA测序的 microRNA 分析显示，在经OTA处理的胚胎中，microRNA-731（miR-731）上调。进一步分析预测PRLRa是miR-731的靶基因。抗miR-731恢复了被OTA降低的PRLRa水平，还恢复了被OTA破坏的前肾形态。这些观察结果表明，暴露于OTA会对斑马鱼的器官发生产生不利影响，miR-731和PRLR信号级联的调节促成了OTA介导的肾脏发育异常。
