Global gene expression changes in human urothelial cells exposed to low-level monomethylarsonous acid

Matthew Medeiros, Xinghui Zheng, Petr Novak, Shawn M. Wnek, Vivian Chyan, Claudia Escudero-Lourdes, A. Jay Gandolfi

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)102-112
Number of pages11
JournalToxicology
Volume291
Issue number1-3
DOIs
StatePublished - Jan 27 2012

Keywords

  • Arsenic
  • Bladder cancer
  • Gene expression
  • Monomethylarsonous acid
  • UROtsa

ASJC Scopus subject areas

  • Toxicology

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