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1 Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA, USA
2 Instituto de Nutricion y Tecnologia de los Alimentos, Universidad de Chile, Santiago, Santiago, Chile
* To whom correspondence should be addressed. E-mail: vulpe{at}berkeley.edu.
The levels at which copper becomes toxic is not clear. Several studies have indicated that copper causes oxidative stress; however, most have tested very high levels of copper exposure. We currently have only a limited understanding of the protective systems that operate in cells chronically exposed to copper. Additionally, the limits of homeostatic regulation are not known making it difficult to define the milder effects of copper excess. Furthermore, a robust assay to facilitate the diagnosis of copper excess and to distinguish mild, moderate, and severe copper overload is needed. In order to address these issues, we have investigated the effects on steady state gene expression of chronic copper overload in a cell culture model system using cDNA microarrays. For this study we utilized cells from genetic models of copper overload -- fibroblast cells from two mouse mutants, C57BL/6-Atp7
Mobr and C57BL/6-Atp7Modap. These cell lines accumulate copper to abnormally high levels in normal culture media due to a defect in copper export from the cell. We identified eleven differentially expressed genes in common using our outlier identification methods. Surprisingly, our results show no evidence of oxidative stress in the copper loaded cells. In addition, candidate components perhaps responsible for a copper specific homeostatic response are identified. The genes that encode for the prion protein and the amyloid-beta precursor protein, two known copper-binding proteins, are up-regulated in both cell lines.
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