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

• Published in: Toxicology and applied pharmacology Vol. 241; no. 2; pp. 202 - 209
• Main Authors: Wnek, S.M., Medeiros, M.K., Eblin, K.E., Gandolfi, A.J.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.12.2009; Elsevier
• Subjects: ARSENIC; Biological and medical sciences; BIOLOGICAL RECOVERY; BIOLOGICAL REPAIR; BLADDER; Bladder cancer; BODY; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - administration & dosage; Carcinogens - toxicity; Cells, Cultured; Chemical agents; Chemical and industrial products toxicology. Toxic occupational diseases; Comet Assay; DISEASES; DNA; DNA Damage; DNA DAMAGES; DNA REPAIR; DNA Repair - drug effects; DNA, Single-Stranded - drug effects; DNA, Single-Stranded - metabolism; Drug Administration Schedule; ELEMENTS; ENZYMES; Humans; Medical sciences; Metals and various inorganic compounds; Monomethylarsonous acid; NEOPLASMS; Nephrology. Urinary tract diseases; NUCLEIC ACIDS; ORGANIC COMPOUNDS; Organometallic Compounds - administration & dosage; Organometallic Compounds - toxicity; ORGANS; Poly(ADP-ribose) Polymerases - metabolism; PROTEINS; RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; Reactive Oxygen Species - metabolism; REPAIR; SEMIMETALS; Spectrometry, Fluorescence; STRAND BREAKS; TOXICITY; Toxicology; Tumors; Tumors of the urinary system; Urinary Bladder - drug effects; Urinary Bladder - metabolism; Urinary Bladder - pathology; Urinary Bladder Neoplasms - chemically induced; Urinary Bladder Neoplasms - pathology; Urinary system involvement in other diseases. Miscellaneous; URINARY TRACT; Urinary tract. Prostate gland; UROtsa; Monomethylarsonous acid; Arsenic; UROtsa; Bladder cancer; DNA damage; Human; Urinary system disease; Exposure; Urinary tract disease; Malignant tumor; Persistence; Carcinogen; Chronic; Urinary system; Urinary bladder; Bladder disease; Lesion; Cancer
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2009.08.016

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.