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

Toxicology. 2012 Jan 27;291(1-3):102-12. doi: 10.1016/j.tox.2011.11.002. Epub 2011 Nov 17.


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 50nM 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cells, Cultured
  • DNA Repair
  • Extracellular Matrix / metabolism
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Humans
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Organometallic Compounds / toxicity*
  • Oxidative Stress / drug effects
  • Protein Array Analysis
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Urinary Bladder Neoplasms / chemically induced
  • Urinary Bladder Neoplasms / metabolism
  • Urothelium / cytology
  • Urothelium / drug effects*
  • Urothelium / metabolism*


  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • Organometallic Compounds
  • monomethylarsonous acid
  • Mitogen-Activated Protein Kinases