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

镉（Cd），其中加拿大排名前五位的生产商，有各种工业用途。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，我们研究了肠道吸收镉作为金属形态（即化学金属物种）的功能，重点是抑制必需金属。在过去的五年中，我们开始研究肠道上皮作为目标组织后，金属摄入。这种上皮经历快速和持续的更新，细胞增殖和成熟是时间和功能相关的现象，一些细胞蛋白质发挥关键作用。我们最近发现，镉可能会修改这些细胞内蛋白质的活性，调节肠细胞的成熟。我们还观察到，肠细胞可能会产生一定的阻力镉，但获得这种阻力的能力有很大的变化与细胞的成熟状态。最后，我们已经表明，有镉在肠细胞中的排泄途径，也预计随着细胞成熟状态而变化。因此，我们计划继续研究镉如何影响细胞成熟过程和肠道功能，并确定对镉的获得性抗性是否是可逆的。此外，由于肠上皮细胞在有毒化合物和药物的代谢中起着关键作用，我们的目标是更好地了解镉在何种程度上可以通过直接或间接的作用来改变这种功能。预期的结果将增加我们的知识：（1）在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.