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Development and application of an adverse outcome pathway framework for understanding and predicting neurotoxicity of development and manganese-induced neurodegeneration


Manganese (Mn) is the twelfth most abundant element in the earth crust. Mn is an essential trace mineral in nutrition that can be (neuro)toxic, especially during developmental stages by unclear mechanisms that suggest additional and improved studies. In this way, adverse outcome pathways (AOPs) are novel tools designed to provide a clear-cut mechanistic representation of critical toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event (MIE), a series of intermediate steps and key events, and an adverse outcome (AO). These AO can be revealed by toxicogenomics approaches, which combines toxicology with genomics or other high throughput molecular profiling technologies such as transcriptomics, proteomics, metabolomics, and epigenomics. Recently, our group using toxicogenomics approaches in alternative animal model have discovered that Mn disrupt several pathways associated with cellular homeostasis, including metal dyshomoestasis, protein metabolism impairment, Alzheimer disease, Huntington disease and Parkinson disease. Hence, in this project I am hypothetisized that if adverse outcome pathways induced by manganese species are conserved cross-species, this must improve the understanding of the unclear neuro(toxicological) mechanisms of this metal and its involving in neurodegeneration. This manner, the present project aim to discover if these pathways alterations are conserved in different models, during different developmental stages. The results this project must to improve the available tool for environmental and human risk assessment associated with the manganese. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HERNANDEZ, RAUL BONNE; DE SOUZA-PINTO, NADJA C.; KLEINJANS, JOS; VAN HERWIJNEN, MARCEL; PIEPERS, JOLANDA; MOTESHAREIE, HOUMAN; BURNSIDE, DANIEL; GOLSHANI, ASHKAN. Manganese-Induced Neurotoxicity through Impairment of Cross-Talk Pathways in Human Neuroblastoma Cell Line SH-SY5Y Differentiated with Retinoic Acid. TOXICS, v. 9, n. 12, . (15/24207-9, 19/27840-5, 16/50483-6)
HERNANDEZ, RAUL BONNE; CARRASCAL, MONTSERRAT; ABIAN, JOAQUIN; MICHALKE, BERNHARD; FARINA, MARCELO; GONZALEZ, YASMILDE RODRIGUEZ; IYIRHIARO, GRACE O.; MOTESHAREIE, HOUMAN; BURNSIDE, DANIEL; GOLSHANI, ASHKAN; et al. Manganese-induced neurotoxicity in cerebellar granule neurons due to perturbation of cell network pathways with potential implications for neurodegenerative disorders. METALLOMICS, v. 12, n. 11, p. 1656-1678, . (16/50483-6, 15/24207-9, 16/00371-7, 14/08990-2)

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