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

肠道上皮作为摄入金属的靶器官：研究镉诱导的 ERK 激活及其对体外和体内肠道功能的相关影响

• 批准号: RGPIN-2017-05106
• 负责人: Jumarie, Catherine
• 金额: $ 1.82万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709952
• 关键词: gut; epithelium; target; organ; ingested

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.

镉（CD）是一种有毒的金属，具有许多工业用途，在大气中存在，逃离水，土壤和沉积物。它通过吸入（在工作场所和吸烟者中）吸收，并摄入受污染的食品。镉的消除量很差，并且保留在体内。它的毒性包括肺阻塞性疾病，肾功能障碍和骨质肌瘤（骨骼软化）。 CD也是致癌物。它由美国环境保护局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CD进入食物链并实际上存在于所有食物中，因此饮食是非吸烟者中环境CD的主要暴露来源。幸运的是，口服吸收的有效性很低。实际上，肠道上皮起着有效的防护屏障，以防止CD吸收，因为它有能力在高水平的积累中捕获CD，从而最大程度地减少进入血液的机会。因此，肠上皮表示CD摄入后的靶组织。然而，很少研究肠道，因为即使口腔接触也是大量污染物的主要吸收途径。我们的NSERC研究计划的总体目标是：i）表征肠道细胞中的金属毒性途径在低水平的暴露水平上可能影响肠道功能； ii）有助于开发更合适的模型，以便在风险评估中进行体内外推。即使在不会导致细胞死亡的低水平下，CD也具有无数的微妙作用，可能会破坏细胞功能。这对于肠上皮尤其至关重要，因为它的快速更新循环涉及通过特定蛋白的选择性激活细胞增殖和成熟的调节。我们已经表明，CD可能会影响其中一些细胞内信号，并且细胞对CD的敏感性取决于增殖或成熟步骤。该程序在接下来的5年中的主要目标是：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道上皮完整性的影响； 3）估计CD可能影响多少CD有助于敏感受试者中炎症性肠病的加剧。我们将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。 这项研究的基本好处是对金属毒性的知识增加。实际的好处是由于使用这些知识来表征毒性途径（从分子事件到细胞反应），从而使更全面的方法可以进行风险评估。