Intestinal exposure to metals: impact on cell differentiation and intestinal cell funtions.

镉（Cd）有多种工业用途，加拿大是五大镉生产国之一。在人类中，两种主要的吸收途径是吸入（职业接触和吸烟者）和通过受污染的食品摄入（一般人群）。几十年来，我们研究了镉的肠道吸收作为金属物种（即化学金属物种）的功能，重点是必需金属的抑制作用。在过去的五年中，我们开始研究肠上皮作为金属摄取后的靶组织。这种上皮受到快速和不断的更新，细胞增殖和成熟是时间和功能相关的现象，其中一些细胞蛋白起关键作用。我们最近的研究表明，Cd可能会改变一些调节肠细胞成熟的细胞内蛋白的活性。我们还观察到肠细胞可能对Cd产生一定的抗性，但获得这种抗性的能力随着细胞成熟状态的不同而有很大差异。最后，我们发现Cd在肠细胞中的排泄途径也会随着细胞成熟状态的变化而变化。因此，我们计划继续研究Cd如何影响细胞成熟过程和肠道功能，并确定对Cd的获得性耐药是否可逆。此外，由于肠上皮在有毒化合物和药物的代谢中起着关键作用，我们希望更好地了解Cd通过直接或间接作用在多大程度上改变了这一功能。预期结果将增加我们对以下方面的认识：(1)细胞水平上的金属毒性机制；(2)如何“慢性”暴露于低水平的金属影响肠道代谢活动，这是毒理学和药理学的极大兴趣。

Cadmium (Cd), for which Canada ranks in the top five producers, has various industrial uses. In humans, the two main routes of absorption are inhalation (occupational exposure and smokers) and ingestion through contaminated food products (general population). During decades we have studied the intestinal uptake of Cd as a function of metal speciation (i.e. chemical metal species) focusing on inhibition by essential metals. During the past five years we began to study the intestinal epithelium as a target tissue following metal ingestion. This epithelium is subjected to rapid and constant renewal for which cellular proliferation and maturation are temporally- and functionally-linked phenomena for which some cellular protein play crucial role. We have recently shown that Cd may modify the activity of some of these intracellular proteins which regulate the intestinal cell maturation. We have also observed that the intestinal cell may develop some resistance to Cd but the capacity to acquire this resistance vary considerably with the cell maturation status. Finally, we have shown that there are excretory pathways for Cd in intestinal cells that are also expected to vary with the cell maturation status. We thus plan to pursue our investigation on how Cd may impact on the cell maturation processes and the intestinal functions, and determine whether the acquired resistance to Cd is reversible. Moreover, because the intestinal epithelium play a critical role in the metabolism of toxic compounds as well as pharmaceutical drugs, we aim better understanding to which extent Cd may modify, by direct or indirect action, this function. The expected results will increase our knowledge on: (1) mechanisms of metal toxicity at the cellular level and; (2) how 'chronic' exposure to low levels of metals affect intestinal metabolism activities which is of great interest for toxicology and pharmacology.