Environmentally Relevant Concentrations of Arsenite Induce Dose-Dependent Differential Genotoxicity Through Poly(ADP-Ribose) Polymerase Inhibition and Oxidative Stress in Mouse Thymus Cells
Authors: Xu, H; Zhou, X; Wen, X; Lauer, FT; Liu, KJ; Hudson, LG; Aleksunes, LM; Burchiel, SW
Toxicological Sciences 149:31-41.
HERO ID: 3379632
Inhibition of DNA repair and oxidative stress are 2 common mechanisms associated with arsenic-induced . . .
Inhibition of DNA repair and oxidative stress are 2 common mechanisms associated with arsenic-induced genotoxicity. The purpose of this study was to examine mechanisms of genotoxicity induced by environmentally relevant doses of arsenite (As(+3)) in mouse thymus cells. An increase in DNA damage and a decrease in poly(ADP-ribose) polymerase (PARP) activity were seen in vitro following exposure to 50 nM As(+3) in primary mouse thymus cells and a murine thymus pre-T cell line, D1. 3,4-Dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline, a well-characterized PARP inhibitor, also produced DNA damage in D1 cells, confirming the correlation between PARP inhibition and DNA damage increase. As(+3) at 500 nM induced double strand breaks (DSBs) in DNA and oxidative stress at 4 h in D1 cells, which was reversed at 18 h. No apoptosis or decrease of viability was observed in these exposures. 4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, a widely-used antioxidant, was utilized to confirm that oxidative stress is partially responsible for the increase of strand breaks in 500 nM As(+3) exposure at 4 h. Expression of As(+3) exporters, Mdr1 and Mrp1, were found to be induced by 500 nM As(+3) in D1 cells, suggesting a possible mechanism for reversal of oxidative stress and DSBs at the 18-h timepoint. Finally, we showed that DNA damage and PARP inhibition by As(+3) were reversed by zinc (Zn(+2)) at approximate equimolar doses. Collectively, these results demonstrate that As(+3) at doses within the nanomolar range induce genotoxicity by inhibiting PARP, and produces oxidative stress at higher concentrations, which can be reversed by a Zn(+2) treatment.