Olfactory manganese uptake in Hfe knockout mice, a model of iron overload

Abstract

Iron deficiency increases dietary Fe absorption due to up‐regulation of divalent metal transporter‐1 (DMT1) in intestinal epithelium. DMT1 also transports Mn and we have shown iron deficiency enhances olfactory Mn uptake to the brain due to iron‐responsive regulation of DMT1 in olfactory epithelium. Understanding the influence of iron homeostasis on olfactory Mn uptake is important due to the neurotoxicity of airborne metal. Whether iron loading alters olfactory Mn uptake is unknown. Hereditary hemochromatosis, an iron overload disease associated with excessive intestinal Fe absorption, is commonly caused by loss of HFE gene function. We have characterized Mn pharmacokinetics in Hfe knockout mice after intravenous and intranasal 54Mn administration. Hfe−/− mice had higher serum and liver iron than Hfe+/+mice, consistent with iron overload status. In contrast, Hfe−/− mice displayed lower blood Mn levels. After intravenous injection, Hfe−/− mice cleared 54Mn from the blood more rapidly than Hfe+/+mice while 54Mn distribution to the brain was similar. However, after intranasal instillation 54Mn brain levels in Hfe−/− mice were elevated indicating olfactory uptake to the brain is enhanced by iron loading. The possible role of DMT1 and other metal transporters in enhanced olfactory Mn absorption to the brain due to HFE‐associated iron loading should be further studied. Supported by NIH DA027030 and ES017781.Grant Funding Source: NIH