Toxicological Sciences 61, 314-320 (2001)
Copyright © 2001 by the Society of Toxicology
MOLECULAR AND GENETIC TOXICOLOGY |
Stress-Related Gene Expression in Mice Treated with Inorganic Arsenicals
* Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute for Environmental Health Sciences, Mail Drop F0-09, Research Triangle Park, North Carolina 27709;
Laboratory of Pharmacology and Chemi-stry, NIEHS, Research Triangle Park, North Carolina 27709; and
University of Kansas Medical Center, Kansas City, Kansas 66160
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 µmol/kg], sodium arsenate [As(V), 300 µmol/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-
(TNF-) 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.
Key Words: arsenite; arsenate; acute toxicity; cDNA microarray; heme oxygenase-1.
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