Expression of selected pathway-marker genes in human urothelial cells exposed chronically to a non-cytotoxic concentration of monomethylarsonous acid

Matthew Medeiros, Tam Minh Le, Daniel Troup, Petr Novak, A Jay Gandolfi

Research output: Contribution to journalArticle

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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 previous microarray analysis revealed only minor changes in gene expression at 1 and 2. months of chronic exposure to MMA(III), contrasting with substantial changes observed at 3. months of exposure. To address the lack of information between 2 and 3. months of exposure (the critical period of transformation), the expression of select pathway marker genes was measured by PCR array analysis on a weekly basis. Cell proliferation rate, anchorage-independent growth, and tumorigenicity in SCID mice were also assessed to determine the early, persistent phenotypic changes and their association with the changes in expression of these selected marker genes. A very similar pattern of alterations in these genes was observed when compared to the microarray results, and suggested that early perturbations in cell signaling cascades, immunological pathways, cytokine expression, and MAPK pathway are particularly important in driving malignant transformation. These results showed a strong association between the acquired phenotypic changes that occurred as early as 1-2. months of chronic MMA(III) exposure, and the observed gene expression pattern that is indicative of the earliest stages in carcinogenesis.

Original languageEnglish (US)
Pages (from-to)421-434
Number of pages14
JournalToxicology Reports
Volume1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Genes
Arsenicals
Arsenic
Microarrays
Gene expression
Association reactions
Cell signaling
Gene Expression
Urothelium
SCID Mice
Cell proliferation
Microarray Analysis
Metabolites
Urinary Bladder Neoplasms
Carcinogenesis
Cells
Cell Proliferation
monomethylarsonous acid
Cytokines
Cell Line

Keywords

  • Arsenic
  • Arsenical
  • Carcinogenesis
  • Gene expression
  • PCR array
  • Urinary bladder
  • Urothelial cells

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Toxicology

Cite this

Expression of selected pathway-marker genes in human urothelial cells exposed chronically to a non-cytotoxic concentration of monomethylarsonous acid. / Medeiros, Matthew; Le, Tam Minh; Troup, Daniel; Novak, Petr; Gandolfi, A Jay.

In: Toxicology Reports, Vol. 1, 01.01.2014, p. 421-434.

Research output: Contribution to journalArticle

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