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

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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. **