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 (iAsIII), monomethylarsonous acid (MMAIII), and dimethylarsinous acid (DMAIII) on immortalized human uroepithelial cells (SV-HUC-1 cells) using cDNA microarray. After exposure for 25 passages to iAsIII (0.5 μM), MMAIII (0.05, 0.1, or 0.2 μM), or DMAIII (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 DMAIII resulted in a gene profile different from that in cells exposed to iAsIII or MMAIII, and that the iAsIII-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-κB (nuclear factor kappa B) activity seen in response to interleukin-1β in iAsIII-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 iAsIII, MMAIII, or DMAIII has different epigenetic effects on urothelial cells and represses NF-κB activity.

Gene Expression Changes and Induction of Cell Proliferation by Chronic Exposure to Arsenic of Mouse Testicular Leydig Cells

“…The role of other factors such as tissue-specific variation, different dosages, and exposure times in the regulation of oxidative stressresponsive genes can not be rule out. A result similar to ours of (no major change in the oxidative stress-related genes from longterm arsenic-treated cells) was reported by microarray analysis (Su et al, 2006). Our present study together with the earlier report of no major changes in oxidative stress-responsive genes from long-term arsenic-treated cells suggest that oxidative stress-related genes may be involved in the carcinogenic process at a time point earlier than the one used in our study.…”

“…All genes had decreased expression with higher (100 ng/ml and 1 μg/ml) concentrations of arsenic, suggesting that arsenic affects the cell mostly through inhibition of gene expression. Similar pattern of downregulation of genes as a choice of arsenic for its effect than upregulation of genes was recently reported using microarray analysis (Su et al, 2006).…”

Interleukin-1 Receptor Type 2 Acts with c-Fos to Enhance the Expression of Interleukin-6 and Vascular Endothelial Growth Factor A in Colon Cancer Cells and Induce Angiogenesis

“…We have previously observed that the expression of intracellular IL1R2 is enhanced in long term arsenic-exposed human urothelial cells (28). Furthermore, we showed that the ectopic expression of IL1R2 activates intracellular IL-1␣ signaling and increases the transcription of IL-6, IL-8, and collagen and the migration of human urothelial cells (17).…”

Arsenate and dimethylarsinic acid in drinking water did not affect DNA damage repair in urinary bladder transitional cells or micronuclei in bone marrow

“…First, arsenic carcinogenesis is cell-type specific, so the use of only transitional cells avoids potentially misleading information from other types of cells in the bladder. Secondly, urothelial cell lines, such as HUC-1 and UROtsa, may have inactivated p53 protein because of transformation with SV40 large T antigen [Rossi et al, 2001;Su et al, 2006]. Studies showed that cells without functional p53 proteins were more sensitive to arsenic and have different cellular responses than cells with functional p53 [Kircelli et al, 2007].…”