Transcriptome Analysis Reveals Distinct Responses to Physiologic versus Toxic Manganese Exposure in Human Neuroblastoma Cells

• Type of Material: Article
• Authors: Jolyn Fernandes, Emory University; Joshua Chandler, Emory University; Loukia N. Lili, Emory University; Karan Uppal, Emory University; Xin Hu, Emory University; Li Hao, Emory University; Young-Mi Go, Emory University; Dean Jones, Emory University
• Language: English
• Date: 2019-07-24
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Fernandes, Chandler, Lili, Uppal, Hu, Hao, Go and Jones
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fgene.2019.00676
• Title of Journal or Parent Work: FRONTIERS IN GENETICS
• Volume: 10
• Issue: JUN
• Start Page: 676
• End Page: 676
• Grant/Funding Information: This work was funded by NIEHS Grants R01 ES023485 (DJ and Y-MG), R21 ES025632 (DJ and Y-MG), P30 ES019776 (DJ), and NIH S10 OD018006 (DJ).
• Keywords: Genetics & Heredity; 21ST-CENTURY; GENE ONTOLOGY; Science & Technology; cell transcriptomics; GLYCOSYLATION; neurotoxicity; adaptive response; DIFFERENTIATION; CHEMOKINE RECEPTOR CXCR4; dose-response; EXPRESSION; IRON; DEATH; PATHWAY; COMPLEX-I; Life Sciences & Biomedicine; metals
• Research Categories: Biology, Genetics; Biology, Neuroscience; Health Sciences, Toxicology

Abstract

Manganese (Mn) is an essential trace element, which also causes neurotoxicity in exposed occupational workers. Mn causes mitochondrial toxicity; however, little is known about transcriptional responses discriminated by physiological and toxicological levels of Mn. Identification of such mechanisms could provide means to evaluate risk of Mn toxicity and also potential avenues to protect against adverse effects. To study the Mn dose-response effects on transcription, analyzed by RNA-Seq, we used human SH-SY5Y neuroblastoma cells exposed for 5 h to Mn (0 to 100 μM), a time point where no immediate cell death occurred at any of the doses. Results showed widespread effects on abundance of protein-coding genes for metabolism of reactive oxygen species, energy sensing, glycolysis, and protein homeostasis including the unfolded protein response and transcriptional regulation. Exposure to a concentration (10 μM Mn for 5 h) that did not result in cell death after 24-h increased abundance of differentially expressed genes (DEGs) in the protein secretion pathway that function in protein trafficking and cellular homeostasis. These include BET1 (Golgi vesicular membrane-trafficking protein), ADAM10 (ADAM metallopeptidase domain 10), and ARFGAP3 (ADP-ribosylation factor GTPase-activating protein 3). In contrast, 5-h exposure to 100 μM Mn, a concentration that caused cell death after 24 h, increased abundance of DEGs for components of the mitochondrial oxidative phosphorylation pathway. Integrated pathway analysis results showed that protein secretion gene set was associated with amino acid metabolites in response to 10 μM Mn, while oxidative phosphorylation gene set was associated with energy, lipid, and neurotransmitter metabolites at 100 μM Mn. These results show that differential effects of Mn occur at a concentration which does not cause subsequent cell death compared to a concentration that causes subsequent cell death. If these responses translate to effects on the secretory pathway and mitochondrial functions in vivo, differential activities of these systems could provide a sensitive basis to discriminate sub-toxic and toxic environmental and occupational Mn exposures.