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Angeline S. Andrew,^1,2,3 Amy J. Warren,¹ Aaron Barchowsky,^1,2,3 Kaili A.Temple,^1,2 Linda Klei,¹ Nicole V. Soucy,¹ Kimberley A. O'Hara,¹ and Joshua W. Hamilton^1,2,3

¹Department of Pharmacology and Toxicology, Dartmouth Medical School, and ²Center for Environmental Health Sciences, Dartmouth College, Hanover, New Hampshire, USA; ³Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA

Abstract

Examining global effects of toxic metals on gene expression can be useful for elucidating patterns of biological response, discovering underlying mechanisms of toxicity, and identifying candidate metal-specific genetic markers of exposure and response. Using a 1,200 gene nylon array, we examined changes in gene expression following low-dose, acute exposures of cadmium, chromium, arsenic, nickel, or mitomycin C (MMC) in BEAS-2B human bronchial epithelial cells. Total RNA was isolated from cells exposed to 3 µM Cd(II) (as cadmium chloride) , 10 µM Cr(VI) (as sodium dichromate) , 3 µg/cm² Ni(II) (as nickel subsulfide) , 5 µM or 50 µM As(III) (as sodium arsenite) , or 1 µM MMC for 4 hr. Expression changes were verified at the protein level for several genes. Only a small subset of genes was differentially expressed in response to each agent: Cd, Cr, Ni, As (5 µM) , As (50 µM) , and MMC each differentially altered the expression of 25, 44, 31, 110, 65, and 16 individual genes, respectively. Few genes were commonly expressed among the various treatments. Only one gene was altered in response to all four metals (hsp90) , and no gene overlapped among all five treatments. We also compared low-dose (5 µM, noncytotoxic) and high-dose (50 µM, cytotoxic) arsenic treatments, which surprisingly, affected expression of almost completely nonoverlapping subsets of genes, suggesting a threshold switch from a survival-based biological response at low doses to a death response at high doses. Key words: arsenic, cadmium, chromium, DNA microarray, hypoxia inducible factor-1, kinase, mitomycin C, nickel, toxicogenomics, toxicoproteomics. Environ Health Perspect 111:825-838 (2003) .