Academic journal article Environmental Health Perspectives

Distinct Gene Expression Profiles in Immortalized Human Urothelial Cells Exposed to Inorganic Arsenite and Its Methylated Trivalent Metabolites

Academic journal article Environmental Health Perspectives

Distinct Gene Expression Profiles in Immortalized Human Urothelial Cells Exposed to Inorganic Arsenite and Its Methylated Trivalent Metabolites

Article excerpt

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.sup.III]), monomethylarsonous acid ([MMA.sup.III]), and dimethylarsinous acid ([DMA.sup.III]) on immortalized human uroepithelial cells (SV-HUC-1 cells) using cDNA microarray. After exposure for 25 passages to [[iAs.sup.III]] (0.5 [micro]M), [MMA.sup.III] (0.05, 0.1, or 0.2 [micro]M), or [DMA.sup.III] (0.2 or 0.5 [micro]M), 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.sup.III] resulted in a gene profile different from that in cells exposed to [iAs.sup.III] or [MMA.sup.III], and that the [iAs.sup.III]-induced gene profile was closest to that in the tumorigenic HUC-l-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 11, showed enhanced expression, a finding confirmed by the reduced increase in NF-[kappa]B (nuclear factor kappa B) activity seen in response to interleukin-1[beta] in [iAs.sup.III]-exposed cells. The expression of 11 genes was suppressed by all three arsenicals. 5-Aza-denxycytidine partially restored the transcription of several suppressed genes, showing that epigenetic DNA methylatinn was probably involved in arsenical-induced gene repression. Our data demonstrate that chronic exposure to [iAs.sup.III]. [MMA.sup.III], or [DMA.sup.III] has different epigenetic effects on urothelial cells and represses NF-[beta]B activity. Key words: eDNA microarray, immortalized urothelial calls, 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://dr.doi.org/[Online 17 August 2005]

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Arsenic intoxication is a worldwide problem. Billions of people in India, Bangladesh, Inner Mongolia, Taiwan, and North and South America have drunk arsenic-contaminated water for many years (National Research Council 1999) and suffer from a variety of arsenic-induced diseases, such as cancer, diabetes, hypertension, and hyperkeratosis (Chen et al. 1992; Haque et al. 2003; Liu et al. 2002). During the past few decades, arsenic carcinogenesis has been extensively studied using a variety of in vitro molecular cytogenetic approaches and in vivo animal models (Chen et al. 2004; Kitchin 2001; Rossman 2003; Waalkes et al. 2004). The carcinogenesis-associated effects of arsenic involve genotoxic damage such as chromosomal abnormalities and oxidative stress (Basu et al. 2001; Hei and Filipic 2004; Rossman 2003). In addition to genetic alterations, arsenic exposure was shown recently to induce both global hypomethylation (Xie et al. 2004) or specific hypomethylation of the cyclin D1 and estrogen receptor-[alpha] genes (Chen et al. 2004) and hypermethylation of the p53 (tumor suppressor protein p53) gene (Mass and Wang 1997). Epigenetic alterations caused by modification of DNA methylation are therefore considered to play crucial roles in arsenic carcinogenesis (Sutherland and Costa 2003).

Microarray technology, which measures changes in gene expression at the transcriptional level, is a powerful tool for studying global cellular responses to toxicants (Waters and Fostel 2004). Numerous reports have demonstrated that genes showing aberrant expression after exposure to inorganic trivalent arsenic are involved in signal transduction, cell proliferation, oxidative stress responses, and DNA repair in a variety of cell systems (Bae et al. …

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