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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00676

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

 Jolyn Fernandes1, Joshua D. Chandler1,  Loukia N. Lili1,  Karan Uppal1, Xin Hu1, Li Hao1, Young-Mi Go1* and  Dean P. Jones1*
  • 1Emory University School of Medicine, United States

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, 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 were associated with amino acid metabolites in response to 10 μM Mn, while oxidative phosphorylation gene set were 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.

Keywords: Dose - response, cell transcriptomics, adaptive response, Neurotoxicity, Metals

Received: 29 Mar 2019; Accepted: 27 Jun 2019.

Edited by:

Joao B. Rocha, Universidade Federal de Santa Maria, Brazil

Reviewed by:

Xiao Chang, Children's Hospital of Philadelphia, United States
Vivek Venkataramani, University Medical Center Göttingen, Germany
Xiaobo Yang, Guangxi Medical University, China
Banthit Chetsawang, Mahidol University, Thailand  

Copyright: © 2019 Fernandes, Chandler, Lili, Uppal, Hu, Hao, Go and Jones. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mx. Young-Mi Go, Emory University School of Medicine, Atlanta, United States, ygo@emory.edu
PhD. Dean P. Jones, Emory University School of Medicine, Atlanta, United States, dpjones@emory.edu