黄曲霉毒素、伏马菌素和亚硝胺在食管癌前病变过程中的联合作用及维生素C的干预作用研究

A large number of studies have shown that lack of vitamin C and the combined effects of aflatoxin, fumonisins and nitrosamine were related with the process of precancerous esophageal cancer, but it still lacks a comprehensive system of population-based case-control studies and laboratory direct evidence. This case-control study based on the evaluation of the nutritional status of populations who were different stage of esophageal cancer, and selected 100 cases of new precancerous cases in Jiangsu Huai'an which was the high esophageal cancer area from 2017 to 2018. According to the same region, the same sex, age difference less than two years, we match 100 normal cases with controls, collect the blood samples, and detect the internal and external exposure levels of three carcinogen. The vitamin c in serum will also be detected, and the diet of cases will be investigated for three days by duplicate portion method. For the laboratory studies, we treat human normal esophageal epithelial cells with aflatoxin, fumonisins and nitrosamine, then intervene with vitamin c , and observe the cytotoxicity, cell cycle, cell apoptosis, related genes expression and effect of vitamin C so that it could verify the results of population studies, find direct evidences about lack of vitamin C and the combined effects of aflatoxin, fumonisins and nitrosamine in the process of precancerous esophageal cancer. All the results will provide a scientific basis for making the precautionary measures of esophageal cancer.

流行病学调查提示黄曲霉毒素、伏马菌素、亚硝胺的联合作用及维生素C缺乏可能在食管癌前病变过程中发挥了重要作用，但仍缺少人群病例对照研究资料和实验室的直接证据。本研究选择江苏淮安食管癌高发区2017-2018年食管癌前病变新筛查患者100例，以同地区、同性别、年龄相差2岁以内匹配健康人100例，应用双份饭法备份研究对象连续3天的膳食，采集血样，通过检测三种致癌物的内外暴露水平和维生素C的营养状况，分析三种致癌物的联合作用及维生素C缺乏与食管癌前病变的关系。同时结合人群研究结果，用黄曲霉毒素、伏马菌素、亚硝胺处理人类食管正常上皮细胞并用维生素C干预，观察三种致癌物的联合作用对人类正常食管上皮细胞周期、凋亡和相关基因表达的影响及维生素C的干预效果，寻找三种致癌物的联合作用和维生素C缺乏与食管癌前病变关系更直接的证据，探讨其在食管癌发生发展中的意义及其机理，为食管癌一级预防措施的制定提供科学依据。

食管癌的发生是多因素共同作用的结果，流行病学调查提示黄曲霉毒素、伏马菌素、亚硝胺的膳食暴露及微量营养素的缺乏可能在食管癌前病变过程中发挥了重要作用。本研究选择江苏淮安食管癌高发区开展病例对照研究，对该地区人群血液和膳食样本中的黄曲霉毒素、伏马菌素和亚硝酸盐水平以及微量元素水平、血清维生素C和氧化应激相关指标进行检测，探究黄曲霉毒素、伏马菌素和亚硝酸盐的内暴露和外暴露之间的关系、微量营养素摄入量与体内营养状况之间的关系，及其与食管癌前病变和氧化损伤之间的关系，同时结合细胞实验，对人群研究的结论进行验证。流行病学调查结果显示饮酒、喜食玉米和腌晒食品为该地区食管癌前病变的危险因素，喜食豆制品为保护因素。而玉米在贮存过程中易被黄曲霉毒素和伏马菌素污染，腌晒食品则常含有较高含量的亚硝酸盐。实验结果进一步发现食管癌前病变组人群的黄曲霉毒素、伏马菌素和亚硝酸盐的内、外暴露水平较高，而膳食硒摄入量、血浆硒、锰、铁、锌含量和血清维生素C含量均较低，且黄曲霉毒素、亚硝酸盐、硒、锰、铁、锌元素和维生素C的结果具有统计学差异，提示江苏淮安地区居民食管癌高发的原因很可能与膳食中黄曲霉毒素和亚硝酸盐的高暴露以及较差的营养状况有关，而黄曲霉毒素和亚硝酸盐的联合暴露和抗氧化营养素如维生素C和硒元素的缺乏可能通过促进氧化损伤从而在食管癌前病变发生发展中起重要作用。体外实验结果验证了AFB1+ FB1+ MNNG的联合染毒对人类正常食管上皮细胞的毒性及机制，而维生素C对MNNG产生的毒性具有保护作用。该研究为食管癌一级预防措施的制定提供科学依据，具有极为重要的科学意义和现实意义。该地区应进一步加强饮用水源、周边环境、土壤植物及食品的保护，落实食管癌防治知识的宣传，通过给群众普及食管癌防治知识并提供合理的膳食指导，加强对主要粮食作物中霉菌毒素的防控工作，让居民逐步建立起健康的生活和饮食习惯，改善营养状况，从而预防食管癌的发生。