Evolutionary neurotoxicology of manganese (Mn) and its implications for Mn‐induced mixed dementia

Abstract Background Manganese (Mn) is an essential element for all living systems, involved in several biological processes, but chronic and/or acute exposure for this metal can lead to adverse outcome pathways, especially neurotoxicity. In this manner; we hypothesized that if these alterations are conserved cross‐species, this must improve the understanding of the toxicological mechanisms of this metal. Thus, this study aimed to investigate the evolutionary neurotoxicology mechanisms of the manganese. Methods Different biological models ( Saccharomyces cerevisiae ‐ yeast, Danio rerio ‐ zebrafish, Mus musculus ‐ cerebellar granular neurons and Homo sapiens ‐ human neuroblastoma SH‐SY5Y cell line) were exposed for chmical species of Mn and studied through different bioanalytical approaches such as cell viability‐MTT‐assay; sensitivity‐gene‐screening assay; b‐galactosidase assay; ribosome profiles; translation protein efficiency assay; semi‐quantitative proteomics ‐ tandem mass tag; metallomics; transcriptomics (human gene expression microarray kit and qRT‐PCR); bioinformatics (gene ontology and prediction of protein‐protein interaction, which were conducted at the String database and the comparative toxicogenomic database respectively. The results were expressed as mean ± SEM of at least 3 experiments; LC50 and statistically significant differences were estimated by ANOVA (analysis of variance followed by Bonferroni’s tests), using the GraphPad Prism 4.0 Software Inc, San Diego, CA, USA Result We revealed that chemical species of Mn2+ (0.001‐1.5 mM) disrupt metal homeostasis (K, Ca, Fe and Cu); protein metabolism, including translation, post‐translation, and protein degradation as well as associated pathways such as those involved in energetics, cell signaling, cell cycle and neurotransmitter metabolism, in a suite of organisms, from yeast to mammalian. Collectively these cross‐talking alteration of cell pathways potentially can explain with more precision the mechanism of neurotoxicity of this metal. Additionally, analysis in the comparative toxicogenomic database suggested that Mn‐induced neurotoxicity shares mechanism with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease; but sometimes involving different genes or proteins, which needs to be considered before drawing comparisons to humans. Conclusion The evolutionary neurotoxicology of the manganese showed in this study represent a new paradigm for Mn‐induced neurotoxicity and neurodegeneration and open a new avenue to study the role of other essential trace elements in similar pathogenic processes.