Persistence of DNA damage following exposure of human bladder cells to chronic monomethylarsonous acid

Toxicol Appl Pharmacol. 2009 Dec 1;241(2):202-9. doi: 10.1016/j.taap.2009.08.016. Epub 2009 Aug 20.


Malignant transformation was demonstrated in UROtsa cells following 52-weeks of exposure to 50 nM monomethylarsonous acid (MMA(III)); the result was the malignantly transformed cell line, URO-MSC. URO-MSC cells were used to study the induction of DNA damage and the alteration of DNA repair enzymes in both the presence of MMA(III) [URO-MSC(+)] and after subsequent removal of MMA(III) [URO-MSC(-)] following chronic, low-level exposure. In the presence of MMA(III), URO-MSC(+) cells demonstrated a sustained increase in DNA damage following 12-weeks of exposure; in particular, a significant increase in DNA single-strand breaks at 12-weeks of exposure consistently elevated through 52 weeks. The persistence of DNA damage in URO-MSC cells was assessed after a 2-week removal of MMA(III). URO-MSC(-) cells demonstrated a decrease in DNA damage compared to URO-MSC(+); however, DNA damage in URO-MSC(-) remained significantly elevated when compared to untreated UROtsa and increased in a time-dependent manner. Reactive oxygen species (ROS) were demonstrated to be a critical component in the generation of DNA damage determined through the incubation of ROS scavengers with URO-MSC cells. Poly (ADP-ribose) polymerase (PARP) is a key repair enzyme in DNA single-strand break repair. URO-MSC(+) resulted in a slight increase in PARP activity after 36-weeks of MMA(III) exposure, suggesting the presence of MMA(III) is inhibiting the increase in PARP activity. In support, PARP activity in URO-MSC(-) increased significantly, coinciding with a subsequent decrease in DNA damage demonstrated in URO-MSC(-) compared to URO-MSC(+). These data demonstrate that chronic, low-level exposure of UROtsa cells to 50 nM MMA(III) results in: the induction of DNA damage that remains elevated upon removal of MMA(III); increased levels of ROS that play a role in MMA(III) induced-DNA damage; and decreased PARP activity in the presence of MMA(III).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinogens / administration & dosage
  • Carcinogens / toxicity*
  • Cells, Cultured
  • Comet Assay
  • DNA Damage*
  • DNA Repair / drug effects
  • DNA, Single-Stranded / drug effects
  • DNA, Single-Stranded / metabolism
  • Drug Administration Schedule
  • Humans
  • Organometallic Compounds / administration & dosage
  • Organometallic Compounds / toxicity*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Reactive Oxygen Species / metabolism
  • Spectrometry, Fluorescence
  • Urinary Bladder / drug effects*
  • Urinary Bladder / metabolism
  • Urinary Bladder / pathology
  • Urinary Bladder Neoplasms / chemically induced
  • Urinary Bladder Neoplasms / pathology


  • Carcinogens
  • DNA, Single-Stranded
  • Organometallic Compounds
  • Reactive Oxygen Species
  • monomethylarsonous acid
  • Poly(ADP-ribose) Polymerases