Environmentally relevant concentrations of arsenite induce dose-dependent differential genotoxicity through poly(ADP-ribose) polymerase inhibition and oxidative stress in mouse thymus cells

Huan Xu, Xixi Zhou, Xia Wen, Fredine T. Lauer, Ke Jian Liu, Laurie G. Hudson, Lauren M. Aleksunes, Scott W. Burchiel

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)31-41
Number of pages11
JournalToxicological Sciences
Volume149
Issue number1
DOIs
StatePublished - Jan 1 2016

All Science Journal Classification (ASJC) codes

  • Toxicology

Keywords

  • arsenic exporters
  • arsenite-induced genotoxicity
  • mouse thymus cells
  • oxidative stress
  • poly(ADP-ribose) polymerase (PARP) inhibition
  • zinc

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