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Pei-Fen Su,¹ Yu-Jie Hu,² I-Ching Ho,¹ Yang-Ming Cheng,¹ and Te-Chang Lee¹

¹Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China; ²Institute of Biopharmaceutical Sciences, National Yang Ming University, Taipei, Taiwan, Republic of China

Abstract
Inorganic arsenic is an environmental carcinogen. The generation of toxic trivalent methylated metabolites complicates the study of arsenic-mediated carcinogenesis. This study systematically evaluated the effect of chronic treatment with sodium arsenite (iAs^III) , monomethylarsonous acid (MMA^III) , and dimethylarsinous acid (DMA^III) on immortalized human uroepithelial cells (SV-HUC-1 cells) using cDNA microarray. After exposure for 25 passages to iAs^III (0.5 µM) , MMA^III (0.05, 0.1, or 0.2 µM) , or DMA^III (0.2 or 0.5 µM) , significant compound-specific morphologic changes were observed. A set of 114 genes (5.7% of the examined genes) was differentially expressed in one or more sets of arsenical-treated cells compared with untreated controls. Expression analysis showed that exposure of cells to DMA^III resulted in a gene profile different from that in cells exposed to iAs^III or MMA^III, and that the iAs^III-induced gene profile was closest to that in the tumorigenic HUC-1-derived 3-methylcholanthrene-induced tumorigenic cell line MC-SV-HUC T2, which was derived from SV-HUC-1 cells by methylcholanthrene treatment. Of the genes affected by all three arsenicals, only one, that coding for interleukin-1 receptor, type II, showed enhanced expression, a finding confirmed by the reduced increase in NF-B (nuclear factor kappa B) activity seen in response to interleukin-1β in iAs^III-exposed cells. The expression of 11 genes was suppressed by all three arsenicals. 5-Aza-deoxycytidine partially restored the transcription of several suppressed genes, showing that epigenetic DNA methylation was probably involved in arsenical-induced gene repression. Our data demonstrate that chronic exposure to iAs^III, MMA^III, or DMA^III has different epigenetic effects on urothelial cells and represses NF-B activity. Key words: cDNA microarray, immortalized urothelial cells, real-time polymerase chain reaction, toxicogenomics, trivalent arsenite, trivalent methylated arsenic compounds. Environ Health Perspect 114: 394-403 (2006) . doi:10.1289/ehp.8174 available via http://dx.doi.org/ [Online 17 August 2005]

Address correspondence to T-C. Lee, Institute of Biomedical Sciences, Academia Sinica, Nankang 115, Taipei, Taiwan, ROC. Telephone: 886-2-26523055. Fax: 886-2-27829142. E-mail: bmtcl@ibms.sinica.edu.tw

Supplementary Material is available online (http://ehp.niehs.nih.gov/members/2005/8174/suppl.pdf) .

This work was supported by National Research Program for Genomic Medicine grants NSC91-3112-B-010-006, NSC92-3112-B-010-019 and NSC93-3112-B-010-005 from the National Science Council, Taiwan, ROC.

The authors declare they have no competing financial interests.

Received 5 April 2005 ; accepted 17 August 2005.