title: Exposure to cobalt causes transcriptomic and proteomic changes in two rat liver derived cell lines.
abstract: Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies.
authors.affiliation: Excet, Inc., Fort Detrick, Maryland, United States of America.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Permenter
authors.affiliation: US Army Center for Environmental Health Research, Fort Detrick, Maryland, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Dennis
authors.affiliation: Naval Research Laboratory, Washington, District of Columbia, United States of America.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Sutto
authors.affiliation: US Army Center for Environmental Health Research, Fort Detrick, Maryland, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Jackson
authors.affiliation: US Army Center for Environmental Health Research, Fort Detrick, Maryland, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: Lewis
authors.affiliation: US Army Center for Environmental Health Research, Fort Detrick, Maryland, United States of America.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
mesh_terms: D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D016000:Cluster Analysis; D003035:Cobalt / Q000494:pharmacology*; D019295:Computational Biology; D004734:Energy Metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D018384:Oxidative Stress; D020543:Proteome; D040901:Proteomics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020543:Proteome; D003035:Cobalt; C018021:cobaltous chloride