伏马菌素B1诱导肝细胞内质网应激的毒理学意义研究

Food safety is still a key public health issue. Contamination of mycotoxins is an important risk factor for food safety. Fumonisins are a group of structurally related mycotoxins produced mainly by Fusarium verticillioides, a field fungus which commonly infects corn and other agricultural products. Of the 15 fumonisin analogs isolated and characterized, fumonisin B1 (FB1) is the most abundant and is toxicologically the most important. FB1-induced toxic effects include hepatotoxicity, nephrotoxicity, neurotoxicity, immunosuppression and carcinogenicity (a possible carcinogen to humans). The cellular mechanisms involved in FB1-induced toxicity include the induction of apoptosis and oxidative stress. Endoplasmic reticulum (ER) stress is activated in response to the accumulation of incorrectly folded proteins in the lumen of ER, which trigger a series of cellular signaling pathways including activation of PERK- eIFa and IRE1-XBP1. It has been shown that ER stress plays an important role in maintaining cellular homeostasis, the pathogenesis of several diseases and toxic effects of certain chemical and biological toxicants. However, there is no data available regarding the functional role of endoplasmic reticulum (ER) stress in FB1-induced toxicity. Our previous data showed that FB1 treatments triggered a significant ER stress response evidenced by activation of PERK and IRE1, the two arms of ER stress response signaling pathways both in cell culture and animal models. Given the biological functions of ER stress, we therefore hypothesized that FB1-induced ER stress may play a critical role in the hepatotoxicity of FB1 Our proposal will systematically test this hypothesis and determine the functional role of ER stress and its associated signaling pathways in hepatotoxicity induced by FB1.

食品安全依然是政府和民众共同关注的重大民生问题，真菌毒素污染则是危害食品安全的重要因素之一。伏马菌素B1(FB1)是污染食品最常见的真菌毒素之一。肝脏是其主要毒理靶器官。在细胞水平上，诱导靶器官细胞凋亡和氧化应激是其产生毒理学效应的主要机制。内质网应激是一种重要的细胞生物学现象，激活内质网应激响应可产生一系列生理性或病理性生物学效应。我们的前期研究发现FB1可在细胞和动物模型中诱发肝细胞内质网应激，激活未折叠蛋白响应。鉴于内质网应激所可能诱发的一系列生物学效应，我们推断，肝细胞的内质网应激与FB1产生的肝毒性可能有着密切关联。本课题将系统论证这一科学推断，解析FB1诱导的肝细胞内质网应激的主要毒理学意义，阐明肝细胞内质网应激在FB1肝毒理学效应中的作用，为有效控制伏马菌素对人类和动物健康的危害提供新的科学依据。

肝脏是食源性真菌毒素FB1主要毒性靶器官。课题组前期研究发现，FB1在细胞和动物模型中均可激活肝细胞内质网应激，鉴于内质网应激是一种可产生多种生物学效应的细胞生物学现象，课题组推测，FB1诱导的内质网应激与其肝毒性有着密切关联。本项目系统解析了FB1诱导的内质网应激与其诱导的细胞凋亡、细胞自噬和氧化应激的相关关系和关联机制，并在动物模型中研究了内质网应激在FB1诱导肝毒性中的作用。研究数据表明，内质网应激响应中的IRE1通路在FB1诱导的肝细胞凋亡中发挥着关键作用，IRE1通路的激活导致了JNK和线粒体通路的激活，进而诱发肝细胞凋亡的发生；内质网应激的发生激活细胞自噬，肝细胞自噬的发生抑制FB1诱导的肝细胞凋亡作用， 而肾细胞自噬的发生则导致肾细胞发生自噬性细胞死亡；FB1诱导的氧化应激导致了内质网应激的发生，并发现FB1激活内质网应激中的IRE1通路与其诱导的氧化应激存在正反馈机制；在动物模型中，内质网应激抑制剂TUDCA可显著降低FB1诱导的肝毒性，并可有效减弱FB1诱导的小鼠体重下降作用。在此基础上，本项目还进行了FB1与重金属镉联合肝毒性及防治的研究。研究数表明，FB1与重金属镉可诱发协同肝毒性，其机制与进一步激活内质网应激中的IRE1通路有关，并发现药食同源植物甘草中的生物活性物质甘草醇可有效减弱FB1/CdCl2诱导的小鼠体重下降和肝毒性，研究成果为拓展对FB1肝毒性的认识和有效防治提供了新的科学依据。