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Studies in hpx mice, a model of inherited transferrin deficiency, have demonstrated that transferrin is essential for iron delivery to the erythron and regulation of expression of hepcidin, a hormone that inhibits dietary iron absorption. Here we address two other putative roles for s transferrin. First, we determined if transferrin is essential for metabolism of metals other than iron. Metal content analysis of fractionated mouse sera indicated that iron was the most abundant metal in transferrin-rich fractions. Organ metal content analysis demonstrated severe imbalances for iron and minimal to moderate imbalances for copper, zinc and manganese in hpx tissues. Analysis of metal-dependent gene expression and organ metal content in a mouse model of inherited hepcidin excess suggested that hpx tissue imbalances in copper, zinc and manganese levels were not all physiologic or specific to primary transferrin deficiency. Second, we tested if transferrin modulates the mobilization of tissue iron stores. Transferrin treatment of hpx mice decreased iron levels in most tissues analyzed. Iron mobilization was independent of hepcidin, as iron levels decreased in hpx mice deficient in hemojuvelin, a membrane protein essential for hepcidin expression. Iron mobilization led to decreased ferritin iron and heavy chain levels. The decrease in liver ferritin iron stores did not match the decrease in total liver iron stores, suggesting that iron was mobilized from multiple storage sites. Overall, our analysis suggests that the primary consequences of transferrin deficiency are largely specific to iron and that transferrin can modulate the mobilization of tissue iron stores. Disclosures: No relevant conflicts of interest to declare.

Abstract 612 Sporadic iron overload has been reported previously in rats but the underlying cause has not been ascertained. In this study, phenotypic analysis of a subpopulation of Wistar rats designated Hsd:HHCL revealed a low incidence of histologically detected liver iron overload. One rat out of 132 screened animals exhibited liver iron accumulation in a predominantly periportal, hepatocellular distribution; this male rat expressed low RNA levels of the iron regulatory hormone hepcidin and low protein levels of transferrin receptor 2, a membrane protein essential for hepcidin expression in humans and mice and mutated in forms of hereditary hemochromatosis, a disease of excessive intestinal iron absorption and progressive tissue iron overload. Sequencing of the transferrin receptor 2 gene in the iron-overloaded rat revealed a novel Ala679Gly polymorphism affecting a highly conserved residue. Quantitative trait locus mapping revealed that a transferrin receptor 2 polymorphism correlated strongly with serum iron and transferrin saturations in male rats. Transfection of Tfr2 expression constructs into tissue culture cell lines revealed that the Gly679 Tfr2 variant is expressed at a lower level than the Ala679 variant. Selective breeding of rats carrying this polymorphism and characterization of iron metabolism in the resulting progeny indicated that homozygosity for the Ala679Gly allele leads to a hemochromatosis phenotype. The Hsd:HHCL rat is the first genetic rat model of hereditary hemochromatosis and may prove useful for understanding the molecular mechanisms underlying the regulation of iron metabolism and the pathogenesis of hereditary hemochromatosis. Disclosures: No relevant conflicts of interest to declare.

Copper is an essential transition metal that plays a fundamental role in the biochemistry of all aerobic organisms. Recent work elucidating the structural mechanisms of copper delivery to superoxide dismutase provides insight into the cell biology of copper metabolism and serves as an example of how to understand the principles governing the incorporation of metals into proteins.

Here we present data on liver metal levels and expression of genes related to iron homeostasis in rhesus monkeys after inhalational manganese exposure. Archived liver samples from rhesus monkeys exposed to 0 (n=6), 0.06 (n=6), 0.3 (n=4) and 1.5 (n=4) mg/m3 manganese inhalation for 65 days were obtained from a published study (“Tissue manganese concentrations in young male rhesus monkeys following subchronic manganese sulfate inhalation” [1]). Samples were analyzed by spectroscopy, immunoblotting and quantitative PCR to assess metal levels and gene expression. Liver manganese and iron levels were linearly correlated although only the intermediate manganese exposure level (0.3 mg Mn/m3) led to a statistically significant increase in liver iron levels. Keywords: Iron, Manganese, Inhalation, Monkey