Aluminum compounds have been observed in various brain regions, and their accumulation has been associated with many neurodegenerative disorders. Neurotoxic effects of aluminum are attributed to reactive oxygen species generation, induction of apoptosis and inflammatory reactions activation. Metalloestrogen activity of aluminum has also been linked to breast cancer progression and metastasis. In this study, taking into account the anti-apoptotic and anti-oxidant activities of estrogens in neuronal cells, which are mediated by estrogen receptors, the possible estrogenic activity of aluminum in SH-SY5Y neuroblastoma cells was studied. Our results showed that aluminum in the form of aluminum chlorohydrate (ACH) exhibited no effect on estrogen receptors transcriptional activation, and differential effect on estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) protein levels. ACH caused reduction in ERβ protein levels, and increase in its mitochondrial localization. ACH-induced reduction in ERβ protein level may be linked, at least in part, to the ACH-induced increase in ERα protein level. This statement is based on our observations showing aluminum-induced reduction in the E2-induced increase in ERα S118 phosphorylation, in MCF-7 and SH-SH5Y cells. Phosphorylation at S118 residue is known to be associated with inhibition of the ubiquitin-induced proteolytic degradation of ERα, leading to its accumulation. Since it is known that ERα negatively regulate ERβ expression, increase in ERα, may contribute to reduction in ERβ levels and subsequent weakening of its anti-apoptotic and anti-oxidant activity, justified by the observed reduction in procaspase 9, mitochondrial cytochrome c, Bcl-2, Bcl-xL and mitochondrial thioredoxin protein level, as well as by the increase in proapoptotic BAX level, in ACH treated SH-SY5Y cells. In addition, increase in mitochondrial ERβ localization may also trigger mitochondrial metabolism, suppress biosynthetic process of gluconeogenesis, as indicated by the observed reduction in the phosphoenolpyruvate carboxykinase protein level, and eventually lead to increase in reactive oxygen species (ROS) generation, known to be implicated in aluminum induced neurodegeneration. This statement was verified by the observed ACH-induced increase in ERβ mitochondrial localization, induction of the mitochondrial membrane depolarization and increase in ROS production, in neuronal-like differentiated SH-SY5Y cells.

中文翻译：

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铝的神经毒性作用与其对雌激素受体信号传导的干扰有关。

铝化合物已经在大脑的各个区域被观察到，它们的积累与许多神经退行性疾病有关。铝的神经毒性作用归因于活性氧的产生，细胞凋亡的诱导和炎症反应的激活。铝的金属雌激素活性也与乳腺癌的进展和转移有关。在这项研究中，考虑到雌激素受体介导的神经元细胞中雌激素的抗凋亡和抗氧化活性，研究了SH-SY5Y神经母细胞瘤细胞中铝的可能雌激素活性。我们的结果表明，铝的水合氯化铝（ACH）形式对雌激素受体的转录激活没有影响，对雌激素受体α（ERα）和雌激素受体β（ERβ）蛋白质水平的影响。ACH导致ERβ蛋白水平降低，线粒体定位增加。ACH诱导的ERβ蛋白水平降低可能至少部分与ACH诱导的ERα蛋白水平升高有关。该陈述是基于我们的观察结果，在MCF-7和SH-SH5Y细胞中，铝诱导的E2诱导的ERαS118磷酸化增加导致铝诱导的减少。已知S118残基的磷酸化与抑制泛素诱导的ERα的蛋白水解降解有关，从而导致ERα积累。由于已知ERα负调节ERβ的表达，因此ERα的增加可能会导致ERβ的水平降低，进而削弱其抗凋亡和抗氧化活性，在ACH处理的SH-SY5Y细胞中，观察到的蛋白酶3，线粒体细胞色素c，Bcl-2，Bcl-xL和线粒体硫氧还蛋白的水平降低，以及促凋亡的BAX水平升高，证明了这一点。此外，线粒体ERβ定位的增加也可能触发线粒体代谢，抑制糖异生的生物合成过程，如所观察到的磷酸烯醇丙酮酸羧激酶蛋白水平的降低，并最终导致活性氧（ROS）生成增加与铝诱导的神经变性有关。通过在神经元样分化的SH-SY5Y细胞中观察到的ACH诱导的ERβ线粒体定位增加，线粒体膜去极化的诱导和ROS产生的增加，证实了这一说法。