Neurotoxic effects of aluminum are associated with its interference with estrogen receptors signaling

• Published in: Neurotoxicology (Park Forest South) 2020-03, Vol.77, p.114-126
• Main Authors: Tsialtas, Ioannis, Gorgogietas, Vyron A., Michalopoulou, Maria, Komninou, Aggeliki, Liakou, Eleni, Georgantopoulos, Achilleas, Kalousi, Foteini D., Karra, Aikaterini G., Protopapa, Evagelia, Psarra, Anna-Maria G.
• Format: Article
• Language: English
• Subjects: Accumulation; Activation; Aluminum; Aluminum - toxicity; Aluminum chlorohydrate; Aluminum compounds; Antioxidants; Apoptosis; BAX protein; Bcl-2 protein; Bcl-x protein; Breast cancer; Cell differentiation; Cell Line, Tumor; Cytochrome; Cytochrome c; Cytochromes; Depolarization; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - metabolism; Estrogen receptors; Estrogenic activity; Estrogens; Gluconeogenesis; Humans; Inflammation; Localization; Membrane potential; Metabolism; Metastases; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Neuroblasts; Neurodegeneration; Neurodegenerative diseases; Neurons - drug effects; Neurons - metabolism; Neurotoxicity; Oxidants; Oxidizing agents; Phosphorylation; Proteins; Reactive Oxygen Species; Receptors; Signal Transduction - drug effects; Xenoestrogens
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2020.01.004

•Aluminum chlorohydrate induces reduction in ERβ protein levels in SH-SY5Y cells.•Aluminum chlorohydrate causes increase in ERα protein levels in SH-SY5Y cells.•Aluminum chlorohydrate blocks the E2 – induced ERα phosphorylation at S118.•Aluminum chlorohydrate causes mitochondrial impairment in SH-SY5Y cells.•Aluminum chlorohydrate induces ROS production in neuronal differentiated SH-SY5Y cells. 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