The human bladder is the most sensitive internal organ to arsenic-induced carcinogenesis. The bladder is exposed to inorganic arsenicals and methylated metabolites both systemically and via the urine. Methylated metabolites of arsenic have been found to be more cytotoxic than inorganic arsenicals. The UROtsa cell, an immortalized human urothelium cell, has become an accepted system for examining the toxic effects of arsenicals to the bladder. Year-long chronic low-level exposure of arsenite [1 microM As(III)] or the more toxic arsenic metabolite [monomethyl-arsonous acid;50 nM MMA(III)] transformed UROtsa cells such that they formed tumors when injected into immuno-deficient mice. Current studies indicate that much shorter exposures (3 months) to low-level MMA(III) is sufficient to allow them to grown in soft agar and form tumors in immuno-deficient mice. These results indicate that MMA (III) causes critical, irreversible events in UROtsa cells in the first 3 months of exposure. Thus the Goal of this proposal is to find the critical events that short-term, low-level As(III) or MMA(III) causes in UROtsa cells resulting in their eventual transition into malignantly transformed cells. To accomplish this goal we will do low-level, short-term (0-3) exposures of UROtsa cells to arsenicals [1 microM As(III) and 50 nM MMA(III)] to determine the minimal exposure and time required to malignantly transform these cells. Once this minimal exposure time point is established we will examine the cells for changes in specific alterations in macromolecules, signaling systems, or regulatory systems resulting in the irreversible changes. Since previous studies have found reactive oxygen species (ROS) generation by low-level exposure to As(III) and MMA(III), we will determine if these early effects of arsenicals on UROtsa cells are mediated by ROS generation. To determine if low-level arsenicals can transform "normal" human bladder cells, primary cultures of human bladder cells will be similarly examined. Lastly pivotal events in the transformation of bladder cells by low-level arsenicals will be examined as possible biomarkers in exposed populations. Overall, these studies will clarify the toxic effects of low-level arsenic in a human bladder model and provide potential biomarkers for arsenic-induced bladder injury.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
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Special Emphasis Panel (ZES1-LWJ-M)
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University of Arizona
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Gonzales, Patricia; Felix, Omar; Alexander, Caitlin et al. (2014) Laboratory dust generation and size-dependent characterization of metal and metalloid-contaminated mine tailings deposits. J Hazard Mater 280:619-26
Severson, Paul L; Vrba, Lukas; Stampfer, Martha R et al. (2014) Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen 775-776:48-54
Boitano, Scott; Hoffman, Justin; Tillu, Dipti V et al. (2014) Development and evaluation of small peptidomimetic ligands to protease-activated receptor-2 (PAR2) through the use of lipid tethering. PLoS One 9:e99140
Sollome, James J; Thavathiru, Elangovan; Camenisch, Todd D et al. (2014) HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4). Cell Signal 26:70-82
Medeiros, Matthew; Le, Tam Minh; Troup, Daniel et al. (2014) Expression Of Selected Pathway-Marker Genes In Human Urothelial Cells Exposed Chronically To A Non-Cytotoxic Concentration Of Monomethylarsonous Acid. Toxicol Rep 1:421-434
Crosbie, Ewan; Sorooshian, Armin; Monfared, Negar Abolhassani et al. (2014) A Multi-Year Aerosol Characterization for the Greater Tehran Area Using Satellite, Surface, and Modeling Data. Atmosphere (Basel) 5:178-197
Miao, Ziheng; Carreón-Diazconti, Concepcion; Carroll, Kenneth C et al. (2014) The impact of biostimulation on the fate of sulfate and associated sulfur dynamics in groundwater. J Contam Hydrol 164:240-50
Ramirez-Andreotta, Monica D; Brusseau, Mark L; Artiola, Janick F et al. (2014) Environmental Research Translation: enhancing interactions with communities at contaminated sites. Sci Total Environ 497-498:651-64
Csavina, Janae; Field, Jason; Félix, Omar et al. (2014) Effect of wind speed and relative humidity on atmospheric dust concentrations in semi-arid climates. Sci Total Environ 487:82-90
Beamer, P I; Sugeng, A J; Kelly, M D et al. (2014) Use of dust fall filters as passive samplers for metal concentrations in air for communities near contaminated mine tailings. Environ Sci Process Impacts 16:1275-81

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