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

R.B. Hernandez*, N.C. de Souza-Pinto, J. Kleinjans, M. van Herwijnen, J. Piepers, H. Moteshareie, D. Burnside, A. Golshani

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)

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.
Original languageEnglish
Article number348
Number of pages21
JournalToxics
Volume9
Issue number12
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • manganese speciation
  • SH-SY5Y
  • neurotoxicity
  • neurodegeneration
  • protein metabolism
  • ALPHA-SYNUCLEIN OVEREXPRESSION
  • REAL-TIME PCR
  • PROTEIN-SYNTHESIS
  • CHEMICAL SPECIATION
  • GENE-EXPRESSION
  • DOWN-REGULATION
  • TOXICITY
  • EXPOSURE
  • FRACTIONATION
  • MUTAGENESIS

Cite this