Persistence of DNA damage following exposure of human bladder cells to chronic monomethylarsonous acid.
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).
Wnek
S M
SM
Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel St., Tucson, AZ 85721, USA.
Medeiros
M K
MK
Eblin
K E
KE
Gandolfi
A J
AJ
D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D004334:Drug Administration Schedule; D006801:Humans; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000473:pathology
D002273:Carcinogens; D004277:DNA, Single-Stranded; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C406082:monomethylarsonous acid; D011065:Poly(ADP-ribose) Polymerases
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