title: Distinct gene expression profiles in immortalized human urothelial cells exposed to inorganic arsenite and its methylated trivalent metabolites.
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 microM), MMA(III) (0.05, 0.1, or 0.2 microM), or DMA(III) (0.2 or 0.5 microM), 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-kappaB (nuclear factor kappa B) activity seen in response to interleukin-1beta 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-kappaB activity.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Su
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Hu
authors.forename: I-Ching
authors.initials: IC
authors.lastname: Ho
authors.forename: Yang-Ming
authors.initials: YM
authors.lastname: Cheng
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009942:Organometallic Compounds / Q000633:toxicity*; D014521:Urethra / Q000166:cytology
chemical_list: D018053:Arsenites; D007375:Interleukin-1; D016328:NF-kappa B; D009942:Organometallic Compounds; C472511:dimethylarsinous acid; C406082:monomethylarsonous acid; D002101:Cacodylic Acid; C015001:arsenite