Effect of hemochromatosis on manganese neurotoxicity

Abstract

ABSTRACT:Manganese (Mn) is an essential element for normal brain function, but excess levels of Mn in the brain are associated with a number of behavioral problems, including motor dysfunction, memory loss and psychiatric disorders. While Mn is known to share iron transporters for cellular uptake, deficiency in the Hfe (hemochromatosis), a cellular iron regulatory protein, affects the activities of iron transporters and impairs iron metabolism. Previously it was shown that Mn uptake into the brain is increased after intranasal exposure to Mn in Hfe-deficient mice, a mouse model of iron overload hereditary hemochromatosis. However, there is limited information about the effect of Hfe deficiency on Mn toxicity after exposure by other routes. Mn exposure is common through ingestion and inhalation in both environmental and occupational settings. Because Hfe deficiency alters iron transporters, and since Mn shares iron transporters, I hypothesize that Hfe deficiency increases Mn toxicity by modulating Mn uptake from the absorption site and deposition into the target organ for Mn toxicity which is the brain after gastric exposure in drinking water and pulmonary exposure to Mn particles. Specific aims are focused on the effect of Hfe deficiency on 1) the expression levels of metal transporters in the brain, gut and lung including alveolar macrophages, 2) levels of Mn, 3) Mn-associated neurobehavioral impairments, and 4) mechanisms of Mn neurotoxicity. This research will enhance the knowledge of Mn exposure and uptake in Hfe-related hemochromatosis, a prevalent iron disorder in the world.