Manganese-Induced Neurotoxicity through Impairment of Cross-Talk Pathways in Human Neuroblastoma Cell Line SH-SY5Y Differentiated with Retinoic Acid

Author(s)

Hernandez, Raul Bonne ^{[1, 2]} ; de Souza-Pinto, Nadja C. ^[3] ; Kleinjans, Jos ^[4] ; van Herwijnen, Marcel ^[4] ; Piepers, Jolanda ^[4] ; Moteshareie, Houman ^[2] ; Burnside, Daniel ^[2] ; Golshani, Ashkan ^[2]

Affiliation

^[1] Univ Fed Sao Paulo, Dept Chem, Lab Bioinorgan & Environm Toxicol LABITA, Rua Prof Artur Riedel 275, BR-09972270 Diadema, SP - Brazil

^[2] Carleton Univ, Dept Biol, 209 Nesbitt Biol Bldg, 1125 Colonel By Dr, Ottawa, ON K1S 5B6 - Canada

^[3] Univ Sao Paulo, Inst Quim, Dept Bioquim, Av Prof Lineu Prestes 748, BR-05508900 Sao Paulo, SP - Brazil

^[4] Maastricht Univ, Dept Toxicogen, Univ Singel 50, Room 4-112, UNS 50, NL-6229 ER Maastricht - Netherlands

• Document type: Journal article
• Source: TOXICS; v. 9, n. 12 DEC 2021.
• Web of Science Citations: 0

Abstract

Manganese (Mn) is an important element; yet acute and/or chronic exposure to this metal has been linked to neurotoxicity and neurodegenerative illnesses such as Parkinson's disease and others via an unknown mechanism. To better understand it, we exposed a human neuroblastoma cell model (SH-SY5Y) to two Mn chemical species, MnCl2 and Citrate of Mn(II) (0-2000 mu M), followed by a cell viability assay, transcriptomics, and bioinformatics. Even though these cells have been chemically and genetically modified, which may limit the significance of our findings, we discovered that by using RA-differentiated cells instead of undifferentiated SH-SY5Y cell line, both chemical species induce a similar toxicity, potentially governed by disruption of protein metabolism, with some differences. The MnCl2 altered amino acid metabolism, which affects RNA metabolism and protein synthesis. Citrate of Mn(II), however, inhibited the E3 ubiquitin ligases-target protein degradation pathway, which can lead to the buildup of damaged/unfolded proteins, consistent with histone modification. Finally, we discovered that Mn(II)-induced cytotoxicity in RA-SH-SY5Y cells shared 84 percent of the pathways involved in neurodegenerative diseases. (AU)

• FAPESP's process: 15/24207-9 - Development and application of an adverse outcome pathway framework for understanding and predicting neurotoxicity of development and manganese-induced neurodegeneration
• Grantee: Raúl Bonne Hernández
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/27840-5 - Toxicogenomics for understanding the evolutionary neurotoxicology of manganese
• Grantee: Raúl Bonne Hernández
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/50483-6 - Modeling in yeast the neurotoxicity and neurodegeneration induced by manganese
• Grantee: Raúl Bonne Hernández
• Support Opportunities: Regular Research Grants