Transcriptional activation and silencing in response to chromium and arsenic

TOXI 107

Aaron Barchowsky, abarchowsky@eoh.pitt.edu1, Kimberley O'Hara1, Antonia A Nemec1, Jawed Alam2, and Linda R. Klei1. (1) Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Bridgeside Poitn, Suite 350, 100 Technology Drive, Pittsburgh, PA 15219, (2) Department of Molecular Genetics, Ochsner Medical Foundation
Airway epithelial cells are primary targets for metal-induced lung disease and cancers. However, overt changes in these cells in response to environmentally or occupationally exposures to metals or metals mixtures are often subtle. Instead, we hypothesized that Cr(VI) promotes lung pathogenesis by silencing cytoprotective genes, such as heme oxygenase-1 (HO-1). Cr(VI) reduced HO-1 mRNA levels in vivo and enhanced As(III)-stimulated apoptosis in cultured human bronchial epithelial (BEAS-2B) cells. Cr(VI) inhibited As(III)-induced BEAS-2B HO-1 expression by preventing Nrf2 DNA binding and transactivation of ARE cis-elements in the ho-1E1 enhancer region. In contrast, Cr(VI) induced a subset of inhibitory interferon response genes by stimulating signal transducer and activator of transcription1 (STAT1). This induction required histone deacetylase activity, which argues against previous theories of Cr(VI) silencing of genes by closing chromatin structure. These data suggest that Cr(VI) promotes injury in lung epithelium by stimulating inhibitory cell signaling. Supported by NIEHS RO1 ES10638.
 

Metal Carcinogenesis: New Concepts
2:00 PM-5:00 PM, Wednesday, 13 September 2006 Moscone Center -- Room 308, Oral

Division of Chemical Toxicology

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006