Toxicological Sciences 61, 283-294 (2001)
Copyright © 2001 by the Society of Toxicology
CARCINOGENICITY |
Sodium Arsenite Enhances AP-1 and NF
B DNA Binding and Induces Stress Protein Expression in Precision-Cut Rat Lung Slices
* Department of Cell Biology and Anatomy and
College of Pharmacy, The University of Arizona, Tucson, Arizona; and
Department of Medical Pharmacology and Toxicology, Texas A&M University System Health Sciences Center, College Station, Texas
Arsenic is a known human carcinogen. These studies were designed to examine the impact of low arsenite concentrations on immediate early gene expression in precision-cut rat lung slices. Precision-cut lung slices are a versatile in-vitro system for toxicity studies, as they preserve the architecture and cellular heterogeneity of the lung. Since 0.1–100 µM arsenite did not compromise slice viability at 4 hours, effects of arsenite on the expression of c-jun/AP-1, NF
B, HSP 32, HSP 72, HSP 60, and HSP 90 were studied, using these concentrations of arsenite at 4 h. Nuclear c-jun was increased by 10 and 100 µM arsenite, while NFB was not affected. Gel-shift assays indicated that 10 µM arsenite resulted in an enhanced DNA-binding activity of both AP-1 and NFB. Confocal microscopic analysis of AP-1 indicated nuclear localization of this transcription factor, mainly in type-II epithelial cells and alveolar macrophages. Nuclear localization of NFB was lower than that observed for AP-1, while most of the NFB was localized to cytoplasm of type-II epithelial cells and alveolar macrophages. HSP 32 was increased by 1.0 and 10 µM arsenite, while HSP 72 was increased by only 100 µM arsenite. HSP 60 and HSP 90 were not changed by arsenite. These studies indicate that noncytotoxic concentrations of arsenite are capable of affecting signal transduction pathways and gene expression in the lung.
Key Words: sodium arsenite; in vitro; precision-cut lung slices; NFB; AP-1; stress proteins.
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