构建体外经口暴露模型评估环境金属毒物的转化吸收和细胞毒性

饮水或土壤中蓄积的重金属通过食物链长期暴露损害人群健康的问题日益突出，而不考虑暴露途径难以准确对重金属污染物经口暴露的健康效应以及风险进行评估。本项目拟构建和优化体外胃、肠液消化体系和肠道粘膜屏障系统，尽可能模拟化学物的消化吸收过程，选择经典环境重金属污染物镉（Cd）、铅（Pb）、铬（Cr）和类金属砷（As），探讨影响金属化学物经口暴露后吸收转运的关键因素，完善重金属化学物经口暴露的PBPK模型参数，并阐明重金属化学物转运率和肠道屏障系统损伤以及靶细胞毒性之间的关系。同时利用转录组测序和计算毒理学技术分析毒性通路扰动与重金属暴露的剂量-反应关系，识别重金属暴露毒性效应的基因表达指纹谱和关键毒性通路，利用反向外推剂量法构建典型重金属化学物外暴露剂量与靶器官剂量的外推模型，评估环境重金属污染物经口暴露的健康风险，为环境化学物以及食品污染物暴露的风险评估提供新的技术手段。

The long-term exposure of heavy metals accumulated in drinking water or soil through the food chain has become an increasingly prominent problem that damages people's health. However, it is difficult to accurately assess the health effects and risks of oral exposure to heavy metal pollutants without considering the exposure pathway. Therefore, this project intends to construct and optimize the digestive system of gastric and intestinal juice and intestinal mucosa barrier system in vitro, simulating the digestion and absorption process of chemicals. Classical environmental heavy metal pollutants cadmium (Cd), lead (Pb), chromium (Cr) and metalloid arsenic (As) will be selected to explore the key factors affecting the absorption and translocation of metal by oral exposure and establish a dose-response relationship model, which will improve the PBPK model parameters of heavy metal chemicals by oral exposure and clarify the correlation between heavy metal transport rate and intestinal barrier system damage as well as target cells toxicity. Meanwhile, we will perform transcriptome sequencing and computer toxicology to analyze the dose-response relationship between toxicity pathway perturbation and heavy metal exposure, identify the gene expression fingerprint spectrum and key toxic pathways induced by heavy metal exposure, construct the extrapolation model between external exposure dose of typical heavy metal chemicals and target organ dose, and assess the health risk of oral exposure of environmental heavy metal pollutants. Our study will provide a new technical tool for risk assessment of environmental chemical exposure and food contaminants.