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)是一种有毒金属，具有多种工业用途，存在于大气、径流、土壤和沉积物中。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。镉被很好地消除了，它仍然留在体内。它的毒性包括肺阻塞性疾病、肾功能障碍和骨软化(骨骼软化)。镉也是一种致癌物质。它被美国环境保护局和加拿大环境与健康局列为优先污染物之一。 由于土壤中的Cd进入食物链，几乎存在于所有食物中，饮食是非吸烟者环境Cd的主要暴露来源。幸运的是，口服吸收的有效性很低。事实上，肠道上皮起到了防止Cd吸收的有效保护屏障的作用，因为它有能力捕获高水平积累的Cd，最大限度地减少对血液的访问。因此，肠上皮是镉摄取后的靶组织。然而，对肠道的研究很少，即使口腔接触也是吸收大量污染物的主要途径。我们NSERC研究计划的主要目标是：i)确定低水平暴露下可能影响肠道功能的肠道细胞中金属毒性途径的特征；ii)为风险评估中的体外-体内外推开发更合适的模型。即使在不会导致细胞死亡的低水平，镉也有无数微妙的影响，可能会扰乱细胞功能。这对肠上皮尤其重要，因为它的快速更新周期涉及到通过选择性地激活特定蛋白质来调节细胞的增殖和成熟。我们已经证明，Cd可能会影响其中一些细胞内信号，细胞对Cd的敏感性取决于细胞的增殖或成熟步骤。该计划未来5年的主要目标是：1)进一步表征Cd干扰特定细胞内信号的方式；2)研究这些干扰对肠道细胞和肠道上皮完整性的影响；3)估计Cd对敏感对象炎症性肠病的加重有多大影响。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，以更好地描述一些基因的作用。 这项研究的根本好处是增加了对金属毒性的了解。使用这一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。