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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

Authors: Wnek, S M; Medeiros, M K; Eblin, K E; Gandolfi, A J

Published In Toxicol Appl Pharmacol, (2009 Dec 1)

Abstract: 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).

PubMed ID: 19699219 Exiting the NIEHS site

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 Neoplasms/chemically induced; Urinary Bladder Neoplasms/pathology; Urinary Bladder/drug effects*; Urinary Bladder/metabolism; Urinary Bladder/pathology

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