Manganese (Mn) is an essential metal and nutrient yet toxic in excess. Mn toxicity has been reported in patients with iron deficiency, patients receiving total parenteral nutrition supplemented with Mn, and miners and welders exposed to Mn rich fumes and particulates through inhalation. In 2012, the first known inherited disease of Mn excess was reported in patients with mutations in SLC30A10, a Mn efflux transporter that is highly expressed in the liver, brain, and duodenum and hypothesized to be essential for Mn excretion. Characterized by increased blood Mn levels, dystonia, polycythemia (increased red blood cell counts), and liver cirrhosis, SLC30A10 deficiency is a novel disease that offers a unique opportunity to investigate systemic Mn regulation. Our long- term objective is to establish mechanisms of Mn homeostasis, significant to the development of novel therapeutic approaches to treat patients with acquired and inherited forms of Mn toxicity. Our preliminary studies indicate that mice globally deficient in Slc30a10 develop tissue Mn excess and polycythemia, similar to patients with SLC30A10 deficiency. As Mn is eliminated predominantly in the feces via hepatobiliary excretion, we hypothesized that hepatocyte-specific Slc30a10 deficiency would lead to a phenotype similar to that of global Slc30a10 deficiency. Surprisingly, mice with hepatocyte Slc30a10 deficiency have only minimal tissue Mn excess. 54Mn excretion studies indicate that global and hepatocyte-specific Slc30a10 deficient mice develop impaired hepatobiiary excretion with intact systemic Mn excretion, suggesting that Mn excess in Slc30a10 deficiency is not a result of impaired Mn excretion. Instead, 54Mn absorption studies indicate that mice with global Slc30a10 deficiency develop increased Mn absorption for unknown reasons. Our immediate goal is to establish the mechanism by which global Slc30a10 deficiency leads to increased Mn absorption. This will be accomplished in two aims: (1) While Slc30a10 is highly expressed in regions of the gastrointestinal tract, the role of intestinal Slc30a10 in Mn homeostasis is unknown.
Aim 1 will determine the contribution of intestinal Slc30a10 to systemic Mn homeostasis by generating and characterizing intestinal-specific Slc30a10-deficient mice. (2) For unknown reasons, mice with global Slc30a10 deficiency develop deficiency in hepcidin, a hormone produced by the liver that inhibits iron absorption through degradation of ferroportin, a metal efflux transporter present in enterocytes. Since ferroportin has also been implicated in Mn homeostasis, hepcidin deficiency may contribute to increased Mn absorption.
Aim 2 will determine if hepcidin deficiency contributes to increased Mn absorption by characterizing the effect of hepcidin treatment on Mn absorption and other phenotypes of global Slc30a10- deficient mice. Overall, this work is fundamental to establishing mechanisms of Mn homeostasis that are invaluable for identifying individuals at risk for Mn toxicity and developing a proper treatment plan for patients with Mn toxicity.
Although an essential nutrient, manganese is toxic in excess. Mechanisms of manganese homeostasis are poorly understood. Projects outlined in this proposal will establish such mechanisms, invaluable to developing treatments for several populations at risk of manganese toxicity.
