Stress-related gene expression in mice treated with inorganic arsenicals.
Arsenic (As) is an environmental chemical of high concern for human health. Acute toxicity of arsenic is dependent on its chemical forms and proximity to high local arsenic concentrations is one of the mechanisms for cell death. This study was designed to define acute arsenic-induced stress-related gene expression in vivo. Mice were injected sc with either sodium arsenite [As(III), 100 micromol/kg], sodium arsenate [As(V), 300 micromol/kg], or saline. To examine stress-related gene expression, livers were removed 3 h after arsenic injection for RNA and protein extraction. The Atlas Mouse Stress/Toxicology array revealed that the expression of genes related to stress, DNA damage, and metabolism was altered by acute arsenic treatments. Expression of heme oxygenase 1 (HO-1), a hallmark for arsenic-induced stress, was increased 10-fold, along with increases in heat shock protein-60 (HSP60), DNA damage inducible protein GADD45, and the DNA excision repair protein ERCC1. Downregulation of certain cytochrome P450 enzymes occurred with arsenic treatment. Multiprobe RNase protection assay revealed the activation of the c-Jun/AP-1 transcription complex after arsenic treatments. Western blot analysis further confirmed the enhanced production of arsenic-induced stress proteins such as HO-1, HSP70, HSP90, metallothionein, the metal-responsive transcription factor MTF-1, nuclear factor kappa B and c-Jun/AP-1. Increases in caspase-1 and cytokines such as tumor necrosis factor-alpha (TNF-alpha) and macrophage inflammatory protein-2 were also evident. In summary, this study profiled the gene expression pattern in mice treated with inorganic arsenicals, which adds to our understanding of acute arsenic poisoning and toxicity.
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Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute for Environmental Health Sciences, Mail Drop F0-09, Research Triangle Park, North Carolina 27709, USA. liu6@niehs.nih.gov
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D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D018053:Arsenites / Q000633:toxicity; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000187:drug effects; D004720:Endonucleases; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000097642:GADD45 Proteins; D000097809:Transcription Factor MTF-1
D001152:Arsenicals; D018053:Arsenites; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D004720:Endonucleases; D006360:Heat-Shock Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008668:Metallothionein; D016328:NF-kappa B; D011506:Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000097642:GADD45 Proteins; D000097809:Transcription Factor MTF-1; C496542:Hmox1 protein, mouse; C499360:Ercc1 protein, mouse