Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.
Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure.
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DOI：
10.1039/c6mt00080k
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发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Kim J
中科院分区：
文献类型：
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作者：
Ye Q;Kim J
大脑中锰（Mn）积累的增加与神经行为缺陷和脑功能受损显著相关。空气中的锰具有较高的全身生物利用度，并且能够直接进入大脑，使其具有高度神经毒性。虽然锰的转运部分由几种铁转运蛋白介导，但这些转运蛋白的表达会因铁调节基因HFE而改变。HFE基因的突变是铁过载疾病遗传性血色素沉着症的主要原因，这是人类常见的遗传疾病之一。然而，HFE突变是否会改变锰诱导的神经毒性尚未得到评估。因此，我们的目标是确定HFE突变在嗅锰暴露后大脑中锰沉积以及由此产生的神经毒性效应中的作用。携带与人类H63D突变同源的H67D HFE突变的小鼠及其对照野生型小鼠每天经鼻滴注不同剂量（0、0.2、1.0和5.0 mg/kg）的氯化锰，持续3天。使用电感耦合等离子体质谱（ICP - MS）测定血液、肝脏和大脑中的锰含量。H67D突变小鼠在血液、肝脏和大多数脑区，尤其是纹状体中的锰含量显著降低，而喂食铁过载饮食的小鼠则没有。此外，铁转运蛋白（一种铁和锰的重要输出蛋白）的mRNA表达在纹状体中上调。另外，在野生型小鼠中，锰暴露后纹状体中脂质过氧化标志物异前列腺素的水平升高，但在H67D小鼠中未改变。总之，我们的结果表明，H67D突变降低了大脑对锰积累的易感性以及吸入锰诱导的相关神经毒性。
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 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 resultant neurotoxic effects after olfactory Mn exposure. Mice carrying H67D HFE mutation that is homologous to 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) 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 blood, liver and most brain regions, especially in the striatum, while mice fed 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 unchanged in H67D mice. Together, our results suggest that H67D mutation provides decreased susceptibility to Mn accumulation in the brain and associated neurotoxicity induced by inhaled Mn.