亚硝胺是环境中广泛存在的化学致癌物，其食品污染与消化道肿瘤密切相关，但对人体致癌效应仍不明确。传统研究限于亚硝胺诱发细胞内遗传毒性及体细胞突变，但组织微环境中免疫细胞产生的细胞外作用直接影响癌症命运。初步研究发现，亚硝胺致食管癌过程中CXCR3特异趋化因子CXCL9/10/11显著升高，CXCR3+免疫细胞渗透相应增加。因此我们认为CXCR3介导免疫细胞趋化和炎症微环境塑造对亚硝胺诱发消化道肿瘤起关键作用。本项目拟利用大鼠、小鼠、CXCR3基因敲除小鼠模型，并建立人源性细胞体外3D共培养和斑马鱼模型，多层面研究CXCR3毒性通路与亚硝胺遗传毒性之间的交互影响及在肿瘤微环境形成中的作用，建立危害特征定量描述模型；在此基础上探讨维生素E靶向干预作用。从而为基于毒性通路的亚硝胺和亚硝酸盐食品安全风险评估提供研究基础，也为探索消化道肿瘤预防策略、降低我国食源性亚硝胺污染导致的健康危害提供科学支持。

Nitrosamines are widespread carcinogens in the environment, its food contamination is closely related to the digestive tract tumor, but the carcinogenic effect to human remains unclear. Traditional studies are limited to intracellular genotoxicity of nitrosamines inducing somatic mutation, but extracellular effect exerted by immune cells in the tissue microenvironment can directly determine cancer fate. Our preliminary study suggested that the CXCR3 specific chemokines CXCL9/10/11 were dramatically elevated in nitrosamine-induced esophageal carcinogenesis, and CXCR3+ immune cells infiltration was increased. Hence we hypothesized that CXCR3-mediated immune cell chemotaxis and the shaping of inflammatory microenvironment play a critical role in nitrosamines-induced gastrointestinal tumorigenesis. In this project, we plan to perform multi-level studies with rats, mice, CXCR3-knockout mice models, and establish the human cells 3D co-culture system as well as zebrafish model, aiming to investigate the CXCR3 toxicity pathway and its interaction with genetoxicity of nitrosamine, and the role of which in the formation of tumor microenvironment, also to establish quantitative models for hazard characterization; Based on above studies, we will further explore the targeted intervention with Vitamin E. Thereby, we prospect to provide fundamental data for the food safety risk assessment of nitosamines and nitrates based on toxicity pathways, as well as scientific support for the probing of strategies for digestive tract cancer prevention and reducing the health hazards caused by foodborne nitrosamines in China.