Zinc oxide nanoparticles-induced reactive oxygen species promotes multimodal cyto- and epigenetic toxicity

Samrat Roy Choudhury, Josue Ordaz, Chiao Ling Lo, Nur P. Damayanti, Feng Zhou, Joseph Irudayaraj

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

In this study we evaluated and correlated the cytotoxic effects of zinc oxide nanoparticles (ZnO-NPs) to the epigenetic modifications, using human embryonic kidney (HEK-293) cells as a model system. Imaging of singlet and total reactive oxygen species (ROS) in ZnO-NPs-treated live cells was performed followed by the evaluation of its effects on cytoskeletal, mitochondrial, and nuclear integrity, and on the expression of ROS responsive genes. Next, we determined the global and locus-specific changes in DNA-methylation at the 3 global genomic repeat sequences namely LINE-1, subtelomeric D4Z4 and pericentromeric NBL2, and at the promoter of selected ROS responsive genes (AOX1, HMOX1, NCF2, SOD3). Our studies revealed severe actin depolymerization, increased release of mitochondrial cytochrome C, and nuclear enlargement in ZnO-NPs-treated cells. At the epigenetic level, we observed global reduction in 5-methylcytosine and increase in 5- hydroxymethylcytosine content. Additionally, we observed significant increase in the expression of Ten-Eleven Translocation (TET)-methylcytosine dioxygenase genes but not in the expression of DNA-methyltransferases (DNMTs). Based on our findings, we suggest that ZnO-NPs induce abundant increase in ROS to promote multimodal structural and functional anomalies in cells. Most importantly, ZnO-NP-induced ROS may promote global hypomethylation in cells by triggering the expression of TET-enzymes, avoiding DNMT interferences. Global DNA demethylation is considered to be the hallmark of the majority of cancers and once acquired this could be propagated to future progenies. The present study, hence, can be used as a platform for the assessment of epigenomic toxicity of ZnO-NPs in humans in the light of its use in commercial products.

Original languageEnglish (US)
Pages (from-to)261-274
Number of pages14
JournalToxicological Sciences
Volume156
Issue number1
DOIs
StatePublished - Mar 1 2017

Fingerprint

Zinc Oxide
Epigenomics
Nanoparticles
Toxicity
Reactive Oxygen Species
Genes
Methyltransferases
DNA
Long Interspersed Nucleotide Elements
5-Methylcytosine
Dioxygenases
Depolymerization
HEK293 Cells
DNA Methylation
Cytochromes
Actins
Cells
Kidney
Imaging techniques
Enzymes

Keywords

  • Cytotoxicity
  • DNA-methylation
  • Epigenetics
  • ZnO-nanoparticles

ASJC Scopus subject areas

  • Toxicology

Cite this

Zinc oxide nanoparticles-induced reactive oxygen species promotes multimodal cyto- and epigenetic toxicity. / Choudhury, Samrat Roy; Ordaz, Josue; Lo, Chiao Ling; Damayanti, Nur P.; Zhou, Feng; Irudayaraj, Joseph.

In: Toxicological Sciences, Vol. 156, No. 1, 01.03.2017, p. 261-274.

Research output: Contribution to journalArticle

Choudhury, Samrat Roy ; Ordaz, Josue ; Lo, Chiao Ling ; Damayanti, Nur P. ; Zhou, Feng ; Irudayaraj, Joseph. / Zinc oxide nanoparticles-induced reactive oxygen species promotes multimodal cyto- and epigenetic toxicity. In: Toxicological Sciences. 2017 ; Vol. 156, No. 1. pp. 261-274.
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