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

镉是一种存在于大气、径流、土壤和沉积物中的有毒金属，具有多种工业用途。它通过吸入（在工作场所和吸烟者）和摄入受污染的食品而被吸收。镉很难被清除，它仍然留在体内。其毒性包括肺阻塞性疾病、肾功能障碍和骨软化症（骨软化）。镉也是一种致癌物质。它被美国环境保护署和加拿大环境与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镉的主要暴露源。幸运的是，口服吸收的有效性很低。事实上，肠道上皮细胞作为一个有效的保护屏障，防止镉的吸收，因为它有能力捕获镉在高水平的积累，最大限度地减少进入血液。因此，肠上皮细胞是镉摄入后的靶组织。然而，肠道很少被研究，即使是口服暴露也是大量污染物吸收的主要途径。我们的NSERC研究计划的总体目标是：i）表征可能影响肠道功能的低暴露水平下肠细胞中的金属毒性途径; ii）为风险评估中的体外-体内外推法开发更合适的模型做出贡献。即使在不引起细胞死亡的低水平下，镉也有无数可能破坏细胞功能的微妙影响。这对于肠上皮细胞尤其重要，因为其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。我们已经表明，镉可能会影响一些这些细胞内的信号，和细胞的敏感性镉的增殖或成熟的步骤而定。该项目未来5年的主要目标是：1）进一步表征镉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）估计镉可能对敏感受试者炎症性肠病的恶化产生多大影响。我们将继续对人类肠道细胞系和转基因小鼠模型进行研究，以更好地描述某些基因的作用。 * 这项研究的基本好处是增加了对金属毒性的了解。使用这些知识来描述毒性途径（从分子事件到细胞反应）的实际益处，从而可以采用更全面的方法来改善风险评估。**

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. **