食品危害物丙烯酰胺诱导神经毒性中MPO/H2O2/HClO分子氧化体系的作用及机制

Many Kinds of hazards are introduced during food processing. Studies on toxicity and mechanism of these hazards might provide scientific evidences for toxicity intervention and the establishment of limit standard. Acrylamide (ACR), a typical chemical hazard produced in the high-temperature starch-based food processing, shows severe neurotoxicity in human body. However, the mechanism is still unclear. Recent studies have found that the activity of myeloperoxidase (MPO) significantly increased in the neurotoxicity induced by ACR, which suggested the expression of MPO might be involved in ACR neurotoxicity mechanism. Based on previous researches on oxidative stress and cranial nerve system injury we predicted that the oxidative stress induced by MPO/H2O2/HClO system might play a role in the ACR neurotoxicity mechanism, on which has still no related reports focused. This project plans to use inhibitor of MPO/H2O2/ HClO, MPO siRNA cells to determine the role of MPO/H2O2/HClO expression in rat neurotoxicity induced by ACR in vivo and in vitro. This study also explores the effect of MPO/H2O2/HClO on the damage of neuron and glial cells induced by ACR. Furthermore, this study attempts to serve new clues for ACR neurotoxicity mechanism and toxicity intervention.

食品加工过程中会生成许多类危害物，研究食品危害物对人体的毒性作用及机制可为毒性干预及限量标准的制定提供科学依据。丙烯酰胺（ACR）是淀粉食品在高温下产生的典型化学危害物，主要导致人体神经毒性伤害，但关于作用机制的报道十分有限。近期研究表明ACR致神经毒性中脑内活性氧水平明显增高同时髓过氧化物酶（MPO）的活性显著增加，基于氧化应激和脑神经细胞损伤的研究基础，我们推测MPO/H2O2/HClO分子氧化体系形成的HClO氧化应激在ACR神经毒性机制中发挥作用。本项目拟通过体内外实验，采用MPO/H2O2/HClO分子体系拮抗剂和MPO siRNA干扰分子表达的手段，分析MPO/H2O2/HClO体系在ACR致大鼠神经毒性机制中的作用，探讨MPO/H2O2/HClO体系分子表达对ACR诱导胶质细胞及神经元损伤的影响。研究结果力争为ACR神经毒性机制及毒性干预研究提供新线索。

本项目阐明了MPO/H2O2体系在食品危害物丙烯酰胺致小鼠神经毒性中的作用，分析了丙烯酰胺对BV-2神经胶质细胞和神经元细胞的毒性及分子机制。进一步探讨了具有巯基供体的N-乙酰-L-半胱氨酸(NAC)及硫辛酸通过抑制细胞内氧化应激改善了食品危害物丙烯酰胺的神经毒性。主要研究结果如下：①阐明了丙烯酰胺对神经小胶质细胞系BV2细胞的毒性及其诱导的线粒体功能失活与细胞生存/死亡信号通路之间的联系。② 揭示了丙烯酰胺对BV2细胞线粒体能量代谢功能的影响细胞内氧化还原状态的影响及对MPO蛋白表达的影响 。③研究了NAC对丙烯酰胺引起的BV2细胞毒性的保护作用。④ 初步探明了硫辛酸缓解了丙烯酰胺诱发的CD-1小鼠神经毒性与脑内MPO的激活。上述研究结果揭示ACR神经毒性作用中MPO/H2O2体系参与的机制，为典型食品危害物ACR神经毒性机制及其干预研究提供新线索。在此项目的资助下，共发表SCI论文4篇。