title: Environmentally Relevant Concentrations of Arsenite Induce Dose-Dependent Differential Genotoxicity Through Poly(ADP-Ribose) Polymerase Inhibition and Oxidative Stress in Mouse Thymus Cells.
abstract: 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.
authors.affiliation: *Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131; and.
authors.forename: Huan
authors.initials: H
authors.lastname: Xu
authors.affiliation: *Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131; and.
authors.forename: Xixi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Xia
authors.initials: X
authors.lastname: Wen
authors.affiliation: *Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131; and.
authors.forename: Fredine T
authors.initials: FT
authors.lastname: Lauer
authors.affiliation: *Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131; and.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
authors.affiliation: *Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131; and.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
authors.affiliation: Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Aleksunes
authors.affiliation: *Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, New Mexico 87131; and sburchiel@salud.unm.edu.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Burchiel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D009152:Mutagenicity Tests; D018384:Oxidative Stress / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000633:toxicity*; D013950:Thymus Gland / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology
chemical_list: D018053:Arsenites; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015032:Zinc; C015001:arsenite
keywords: arsenic exporters; arsenite-induced genotoxicity; mouse thymus cells; oxidative stress; poly(ADP-ribose) polymerase (PARP) inhibition; zinc