The gut epithelium as a target organ of ingested metals: investigating Cd-induced ERK activation and the related impatcs on intestinal function in vitro and in vivo

镉（Cd）是一种有毒金属，有许多工业用途，存在于大气中，从水、土壤和沉积物中流失。它通过吸入（在工作场所和吸烟者）和摄入受污染的食品吸收。镉很难被清除，它会留在体内。它的毒性包括肺阻塞性疾病、肾功能障碍和骨软化。Cd也是一种致癌物。它被美国环境保护署以及加拿大环境和卫生部列为优先污染物之一。***由于土壤中的镉进入食物链，几乎存在于所有食物中，饮食是非吸烟者环境中镉的主要暴露源。幸运的是，口服吸收的效果很低。事实上，肠道上皮作为一个有效的保护屏障，防止Cd的吸收，因为它有能力在高水平的积累中捕获Cd，最大限度地减少进入血液的机会。因此，肠上皮是镉摄入后的靶组织。然而，很少对肠道进行研究，因为即使是口服暴露也是大量污染物吸收的主要途径。我们NSERC研究计划的总体目标是：i)表征可能影响肠道功能的低水平暴露下肠细胞中的金属毒性途径；Ii)为风险评估中的体内外推断提供更合适的模型。即使在不引起细胞死亡的低水平，镉也有无数微妙的影响，可能会破坏细胞功能。这对肠上皮尤其重要，因为它的快速更新周期涉及通过选择性激活特定蛋白质来调节细胞增殖和成熟。我们已经证明Cd可能影响这些细胞内信号中的一些，并且细胞对Cd的敏感性取决于增殖或成熟步骤。该计划未来5年的主要目标是：1)进一步表征Cd破坏特定细胞内信号的方式；2)研究这些扰动对肠细胞和肠上皮完整性的影响；3)估计敏感性受试者中Cd对炎症性肠病加重的影响程度。我们将继续在人类肠道细胞系和转基因小鼠模型上进行研究，以更好地描述某些基因的作用。这项研究的根本好处是增加了对金属毒性的认识。利用这些知识来描述毒性途径（从分子事件到细胞反应）的实际好处是允许采用更全面的方法来改进风险评估。**

Cadmium (Cd) is a toxic metal with many industrial uses that is present in atmosphere, run off water, soil and sediment. It is absorbed through inhalation (in work places and for tobacco smokers), and ingestion of contaminated food products. Cadmium is poorly eliminated and it remains in the body. Its toxicity includes pulmonary obstructive diseases, kidney dysfunction, and osteomalacia (bones softening). Cd is also a carcinogen. It is listed by the US Environmental Protection Agency as well as by Environment and Health Canada as one of priority pollutants. ***Because Cd in soil enters the food chain and is present virtually in all food, the diet is the main exposure source of environmental Cd in non-smoker. Fortunately, the effectiveness of oral absorption is low. Indeed, the gut epithelium acts as an efficient protective barrier against Cd absorption because it has the capacity to trap Cd at high levels of accumulation, minimizing access to the bloodstream. Consequently the intestinal epithelium represents a target tissue following Cd ingestion. Yet the gut is rarely studied as such even oral exposure is the main route of absorption for a huge number of pollutants. The overarching objectives of our NSERC research program are: i) to characterize metal toxicity pathways in the intestinal cell at low levels of exposure that may affect the gut function; ii) to contribute to the development of more appropriate models for the in vitro-in vivo extrapolation in risk assessment. Even at low levels that do not cause cell death, Cd has myriad subtle effects that may disrupt cell functions. This is especially critical for the intestinal epithelium because of its rapid renewal cycle that involves regulation of cell proliferation and maturation via the selective activation of specific proteins. We have shown that Cd may affect some of these intracellular signals, and that cell's sensitivity to Cd varies depending on the proliferation or the maturation step. The main objectives of the program for the next 5 years are to: 1) further characterize the way Cd disrupts specific intracellular signals; 2) study the impacts these perturbations have on the intestinal cell and the gut epithelium integrity; 3) estimate how much Cd may affect contribute to the exacerbation of inflammatory bowel diseases in sensitive subjects. We will pursue our study on human intestinal cell lines and on transgenic mice models to better delineate the role of some genes. ***The fundamental benefits of this research are increased knowledge on metal toxicity. The practical benefits arise from the use of this knowledge to characterize toxicity pathways (from molecular event to cellular response) allowing a more comprehensive approach to imporve risk assessment. **