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Publication Detail

Title: Interdependent genotoxic mechanisms of monomethylarsonous acid: role of ROS-induced DNA damage and poly(ADP-ribose) polymerase-1 inhibition in the malignant transformation of urothelial cells.

Authors: Wnek, Shawn M; Kuhlman, Christopher L; Camarillo, Jeannie M; Medeiros, Matthew K; Liu, Ke J; Lau, Serrine S; Gandolfi, A J

Published In Toxicol Appl Pharmacol, (2011 Nov 15)

Abstract: Exposure of human bladder urothelial cells (UROtsa) to 50 nM of the arsenic metabolite, monomethylarsonous acid (MMA(III)), for 12 weeks results in irreversible malignant transformation. The ability of continuous, low-level MMA(III) exposure to cause an increase in genotoxic potential by inhibiting repair processes necessary to maintain genomic stability is unknown. Following genomic insult within cellular systems poly(ADP-ribose) polymerase-1 (PARP-1), a zinc finger protein, is rapidly activated and recruited to sites of DNA strand breaks. When UROtsa cells are continuously exposed to 50 nM MMA(III), PARP-1 activity does not increase despite the increase in MMA(III)-induced DNA single-strand breaks through 12 weeks of exposure. When UROtsa cells are removed from continuous MMA(III) exposure (2 weeks), PARP-1 activity increases coinciding with a subsequent decrease in DNA damage levels. Paradoxically, PARP-1 mRNA expression and protein levels are elevated in the presence of continuous MMA(III) indicating a possible mechanism to compensate for the inhibition of PARP-1 activity in the presence of MMA(III). The zinc finger domains of PARP-1 contain vicinal sulfhydryl groups which may act as a potential site for MMA(III) to bind, displace zinc ion, and render PARP-1 inactive. Mass spectrometry analysis demonstrates the ability of MMA(III) to bind a synthetic peptide representing the zinc-finger domain of PARP-1, and displace zinc from the peptide in a dose-dependent manner. In the presence of continuous MMA(III) exposure, continuous 4-week zinc supplementation restored PARP-1 activity levels and reduced the genotoxicity associated with MMA(III). Zinc supplementation did not produce an overall increase in PARP-1 protein levels, decrease the levels of MMA(III)-induced reactive oxygen species, or alter Cu-Zn superoxide dismutase levels. Overall, these results present two potential interdependent mechanisms in which MMA(III) may increase the susceptibility of UROtsa cells to genotoxic insult and/or malignant transformation: elevated levels of MMA(III)-induced DNA damage through the production of reactive oxygen species, and the direct MMA(III)-induced inhibition of PARP-1.

PubMed ID: 21925530 Exiting the NIEHS site

MeSH Terms: Blotting, Western; Carcinogens/toxicity*; Cell Line; Cell Transformation, Neoplastic/drug effects*; Cell Transformation, Neoplastic/metabolism; Chlorides/pharmacology; Comet Assay; DNA Damage/drug effects*; Flow Cytometry; Humans; Organometallic Compounds/toxicity*; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors*; Poly(ADP-ribose) Polymerases/metabolism; Reactive Oxygen Species/metabolism*; Urinary Bladder Neoplasms/chemically induced; Urinary Bladder/cytology; Urinary Bladder/drug effects*; Urothelium/cytology; Urothelium/drug effects*; Zinc Compounds/pharmacology

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