title: Evaluation of gene expression changes in human primary lung epithelial cells following 24-hr exposures to inorganic arsenic and its methylated metabolites and to arsenic trioxide.
abstract: The concentration response for altered gene expression in primary lung epithelial cells was determined following two treatments with arsenicals: (1) a mixture of trivalent arsenic compounds representative of urinary arsenic concentrations in exposed human populations, and (2) arsenite (As2 O3 ) a common form of inhaled arsenic dust that is frequently used in both in vivo and in vitro experimental exposures. Biochemical assays did not detect any evidence of cytotoxicity at the concentrations used, apart from a concentration-related increase in cellular heme oxygenase that was also indicated by the genomic analysis. Cell signal pathway enrichment analysis indicated similar responses to both treatments, with concentration-related responses in pathways related to cell adhesion, cytoskeleton remodeling, development (morphogenesis), cell cycle control, and to a lesser extent inflammatory responses. These cellular responses to arsenic were consistent with those observed in a previous study with primary uroepithelial cells. Benchmark dose analysis also demonstrated similar potency of the two treatments as well as comparable sensitivity of the two cell types. A number of genes showing similar concentration-dependent expression across individuals in both bladder and lung cells were identified, including heme oxygenase 1, thioredoxin reductase, DNA damage binding protein 2, and thrombomodulin. The data on human primary lung cells from this study, together with the data from human primary uroepithelial cells, support a conclusion that biological responses to arsenic by human cells under study conditions are unlikely to occur at concentrations below 0.1 µM. Environ. Mol. Mutagen. 56:477-490, 2015. © 2015 Wiley Periodicals, Inc.
authors: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina.
authors: Alina Y
authors: AY
authors: Efremenko
authors: Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors: JeanClare
authors: J
authors: Seagrave
authors: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina.
authors: Harvey J
authors: HJ
authors: Clewell
authors: ENVIRON International Corporation, Monroe, Louisiana.
authors: Cynthia
authors: C
authors: Van Landingham
authors: ENVIRON International Corporation, Monroe, Louisiana.
authors: P Robinan
authors: PR
authors: Gentry
authors: ENVIRON International Corporation, Emeryville, California.|Division of Epidemiology, Biostatistics and Preventive Medicine, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico.
authors: Janice W
authors: JW
authors: Yager
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism; D018053:Arsenites / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000378:metabolism / Q000633:toxicity*; D061251:Primary Cell Culture; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D001152:Arsenicals; D018053:Arsenites; D003470:Culture Media; C508600:IL6 protein, human; D015850:Interleukin-6; D010087:Oxides; D018808:Transcription Factor AP-1; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D000077237:Arsenic Trioxide
keywords: arsenic; benchmark dose; gene expression; mode of action; primary human lung cells