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1 National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Chapel Hill, NC, USA
2 Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, NC, USA
3 Department of Biochemistry, State University of New York, Buffalo, NY, USA
4 Department of Internal Medicine, Duke University Medical Center, Durham, NC, USA
5 Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
* To whom correspondence should be addressed. E-mail: ghio.andy{at}epa.gov.
Despite a lack of transferrin, hypotransferrinemic (Hp) mice demonstrate an accumulation of iron in peripheral organs including the lungs. One potential candidate for such transferrin-independent uptake of iron is DMT1, an established transporter of iron. We tested the hypothesis that increased concentrations of iron in the lungs of Hp mice are associated with elevations in DMT1 expression. Using inductively coupled plasma emission spectroscopy, measurements of non-heme iron confirmed significantly elevated concentrations in the lung tissue of Hp mice relative to the wild-type mice. Western blot analyses for the expression of two isoforms of DMT1 in the Hp mice relative to the wildtype animals demonstrated an elevation for the isoform that lacks an iron responsive element (IRE) with significant decrements in the expression of +IRE DMT1. Using immunohistochemistry, -IRE DMT1 was localized to both airway epithelial cells and alveolar macrophages in wild-type mice. Staining appeared increased in both types of cells in the Hp mice. Elevated concentrations of both tissue nonheme iron and expression of -IRE DMT1 in the Hp mice were associated with increased quantities of -IRE mRNA. There was no difference between wild-type and homozygotic Hp mice in the amount of mRNA for DMT1 +IRE. We conclude that differences between Hp and wild-type mice in nonheme iron concentrations were accompanied by increases in the expression of -IRE DMT1. Increased expression of -IRE DMT1 in the lungs of the Hp mice could be responsible for elevated concentrations of the metal in these tissues.
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