Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells.
Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells.
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DOI：
10.3233/jad-2005-8204
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
P. Alexandrov;Yuhai Zhao;A. Pogue;M. Tarr;T. Kruck;M. Percy;J. Cui;W. Lukiw
中科院分区：
文献类型：
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作者：
P. Alexandrov;Yuhai Zhao;A. Pogue;M. Tarr;T. Kruck;M. Percy;J. Cui;W. Lukiw
金属离子转运、体内平衡、过载和金属离子介导的催化中的干扰与神经退行性疾病如阿尔茨海默病（AD）有关。金属离子引起的遗传功能破坏的机制，称为遗传毒性，还没有得到很好的理解。在这些实验中，我们研究了非凋亡浓度的镁，铁和铝硫酸盐对基因表达模式的未转化的人神经（HN）细胞在原代培养中，使用高密度DNA阵列分析和Western免疫测定。将两周龄的HN细胞暴露于低微摩尔镁、铁或铝7天，这表示在其寿命的三分之一内暴露于痕量金属。虽然总RNA产量和丰度没有显著改变，但发现铁和铝都诱导HSP 27、考克斯-2、betaAPP和DAXX基因表达。在AD脑中已经观察到这些应激感测、促炎和促凋亡元件的类似上调基因表达。发现铁和铝的组合在上调这些基因中特别有效，并且在此之前是活性氧中间体的演变，如通过2 '，7'-二氯荧光素二乙酸酯测定所测量的。这些数据表明，生理相关量的铁和铝能够诱导芬顿化学触发的基因表达程序，这可能支持下游致病反应和脑细胞功能障碍。
Disturbances in metal-ion transport, homeostasis, overload and metal ion-mediated catalysis are implicated in neurodegenerative conditions such as Alzheimer's disease (AD). The mechanisms of metal-ion induced disruption of genetic function, termed genotoxicity, are not well understood. In these experiments we examined the effects of non-apoptotic concentrations of magnesium-, iron- and aluminum-sulfate on gene expression patterns in untransformed human neural (HN) cells in primary culture using high density DNA array profiling and Western immunoassay. Two week old HN cells were exposed to low micromolar magnesium, iron, or aluminum for 7 days, representing trace metal exposure over one-third of their lifespan. While total RNA yield and abundance were not significantly altered, both iron and aluminum were found to induce HSP27, COX-2, betaAPP and DAXX gene expression. Similarly up-regulated gene expression for these stress-sensing, pro-inflammatory and pro-apoptotic elements have been observed in AD brain. The combination of iron and aluminum together was found to be particularly effective in up-regulating these genes, and was preceded by the evolution of reactive oxygen intermediates as measured by 2',7'-dichlorofluorescein diacetate assay. These data indicate that physiologically relevant amounts of iron and aluminum are capable of inducing Fenton chemistry-triggered gene expression programs that may support downstream pathogenic responses and brain cell dysfunction.