Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity

项目摘要/摘要 锰是许多细胞过程中必不可少的辅因子，但在浓度升高时， 已知对大脑产生神经毒性作用。到目前为止，对接触锰的儿童和 电焊工一直表明，慢性接触锰(X)与运动和运动障碍有关 神经行为结果(Y)。此外，磁共振成像(MRI)显示，两种锰 暴露和结果与大脑中的锰积累(M)有关。虽然这些协会已经提出了 对开发基于成像的安全指南感兴趣，目前尚不清楚大脑MN如何 蓄积可能在锰暴露与运动和神经行为结果之间的关系中起中介作用 (X→M→Y)。这种缺乏理解导致一些人尝试进行复杂的、高维的数据分析 去卷积控制锰暴露个体神经毒性的潜在关系。然而，到目前为止，几乎没有人 解释了常见的基因变异，这些变异可能具有显著的缓和效应。重要的是 已知锰水平受铁(Fe)水平和铁调节蛋白表达的影响。化学上 类似地，锰和铁通过共享的运输机制在细胞内和细胞外的隔室之间移动。 人类血色沉着症蛋白(HFe)是一种铁调节蛋白，它负向调节机制 促进锰进入大脑。63位HFE组氨酸到天冬氨酸的取代(H63D)是 通常携带的导致HFE部分功能丧失的基因变异。因此，这一点的中心假设 联谊应用是HFE H63D调节焊接、脑内锰积累、 以及神经行为和运动结果。在此过程中，H63D可能会缓解长时间的神经毒性效应 锰暴露。揭示这些效应具有特殊的意义。

PROJECT SUMMARY/ABSTRACT Manganese (Mn) is an essential cofactor for many cellular processes, but at elevated concentrations is known to exert neurotoxic effects on the brain. To date, population-based studies of Mn-exposed children and welders have consistently shown that chronic Mn exposure (X) is associated with deficits in motor and neurobehavioral outcomes (Y). Additionally, magnetic resonance imaging (MRI) has shown that both Mn exposure and outcomes are associated with brain Mn accumulation (M). While these associations have raised interest in the development of imaging-based safety guidelines, it is presently unknown as to how brain Mn accumulation may mediate the relationship between Mn exposure and motor and neurobehavior outcomes (X→M→Y). This lack of understanding has led some to attempt complex, high-dimensional data analyses to deconvolve the underlying relationships governing neurotoxicity in Mn-exposed individuals. However, few so far have accounted for common genetic variants that are likely to have significant moderating effects. Importantly, Mn levels are known to be influenced by iron (Fe) levels and the expression of Fe-regulatory proteins. Chemically similar, Mn and Fe move between intra- and extracellular compartments through shared transport mechanisms. The human hemochromatosis protein (HFE) is an Fe-regulatory protein that negatively regulates mechanisms facilitating Mn entry into the brain. The HFE histidine-to-aspartate substitution at position 63 (H63D) is a commonly carried gene variant that results in HFE partial loss-of-function. Thus, the central hypothesis of this fellowship application is that HFE H63D moderates the relationships between welding, brain Mn accumulation, and neurobehavioral and motor outcomes. In doing so, H63D may moderate the neurotoxic effects of prolonged Mn exposure. Uncovering these effects is of particular