Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.
Increased accumulation of manganese (Mn) in the brain is significantly associated with neurobehavioral deficits and impaired brain function. Airborne Mn has a high systemic bioavailability and can be directly taken up into the brain, making it highly neurotoxic. While Mn transport is in part mediated by several iron transporters, the expression of these transporters is altered by the iron regulatory gene, HFE. Mutations in the HFE gene are the major cause of the iron overload disorder, hereditary hemochromatosis, one of the prevalent genetic diseases in humans. However, whether or not HFE mutation modifies Mn-induced neurotoxicity has not been evaluated. Therefore, our goal was to define the role of HFE mutation in Mn deposition in the brain and the resultant neurotoxic effects after olfactory Mn exposure. Mice carrying the H67D HFE mutation, which is homologous to the H63D mutation in humans, and their control, wild-type mice, were intranasally instilled with MnCl2 with different doses (0, 0.2, 1.0 and 5.0 mg kg(-1)) daily for 3 days. Mn levels in the blood, liver and brain were determined using inductively-coupled plasma mass spectrometry (ICP-MS). H67D mutant mice showed significantly lower Mn levels in the blood, liver, and most brain regions, especially in the striatum, while mice fed an iron-overload diet did not. Moreover, mRNA expression of ferroportin, an essential exporter of iron and Mn, was up-regulated in the striatum. In addition, the levels of isoprostane, a marker of lipid peroxidation, were increased in the striatum after Mn exposure in wild-type mice, but were unchanged in H67D mice. Together, our results suggest that the H67D mutation provides decreased susceptibility to Mn accumulation in the brain and neurotoxicity induced by inhaled Mn.
Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue 148TF, Boston, MA 02115, USA. j.kim@neu.edu.
Qi
Q
Ye
Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue 148TF, Boston, MA 02115, USA. j.kim@neu.edu.
Jonghan
J
Kim
D000818:Animals; D000071020:Hemochromatosis Protein / Q000235:genetics*; D008297:Male; D008345:Manganese / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D066194:Olfactory Cortex / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*
D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D008345:Manganese