Journal
TOXICOLOGY
Volume 291, Issue 1-3, Pages 102-112Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2011.11.002
Keywords
Arsenic; Monomethylarsonous acid; Bladder cancer; UROtsa; Gene expression
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Funding
- National Institute of Environmental Health Sciences [ES04940]
- Trainee in Toxicology and Toxicogenomics (NIEHS) [ES007091]
- Southwest Environmental Health Sciences Center (NIEHS) [ES06694]
- Academy of Sciences of the Czech Republic [AVOZ50510513]
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Bladder cancer has been associated with chronic arsenic exposure. Monomethylarsonous acid [MMA(III)] is a metabolite of inorganic arsenic and has been shown to transform an immortalized urothelial cell line (UROtsa) at concentrations 20-fold less than arsenite. MMA(III) was used as a model arsenical to examine the mechanisms of arsenical-induced transformation of urothelium. A microarray analysis was performed to assess the transcriptional changes in UROtsa during the critical window of chronic 50 nM MMA(III) exposure that leads to transformation at 3 months of exposure. The analysis revealed only minor changes in gene expression at 1 and 2 months of exposure, contrasting with substantial changes observed at 3 months of exposure. The gene expression changes at 3 months were analyzed showing distinct alterations in biological processes and pathways such as a response to oxidative stress, enhanced cell proliferation, anti-apoptosis, MAPK signaling, as well as inflammation. Twelve genes selected as markers of these particular biological processes were used to validate the microarray and these genes showed a time-dependent changes at 1 and 2 months of exposure, with the most substantial changes occurring at 3 months of exposure. These results indicate that there is a strong association between the acquired phenotypic changes that occur with chronic MMA(III) exposure and the observed gene expression patterns that are indicative of a malignant transformation. Although the substantial changes that occur at 3 months of exposure may be a consequence of transformation, there are common occurrences of altered biological processes between the first 2 months of exposure and the third, which may be pivotal in driving transformation. Published by Elsevier Ireland Ltd.
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