title: Zinc-Oxide Nanoparticles Exhibit Genotoxic, Clastogenic, Cytotoxic and Actin Depolymerization Effects by Inducing Oxidative Stress Responses in Macrophages and Adult Mice.
abstract: Zinc oxide nanoparticles (ZnO-NPs) have wide biological applications, which have raised serious concerns about their impact on the health and environment. Although, various studies have shown ZnO-NP toxicity on different cells underin vitroconditions, sufficient information is lacking regarding toxicity and underlying mechanisms underin vivoconditions. In this work, we investigated genotoxic, clastogenic, and cytotoxic effects of ZnO-NPs on macrophages and in adult mice. ZnO-NP-treated mice showed signs of toxicity such as loss in body weight, passive behavior and reduced survival. Further mechanistic studies revealed that administration of higher dose caused severe DNA damage in peripheral blood and bone marrow cells as evident by the formation of COMET tail, micronuclei, chromosomal fragmentation, and phosphorylation of H2A histone family member X. Moreover, ZnO-NPs inhibited DNA repair mechanism by downregulating the expression offen-1andpolBproteins. Histopathological examinations showed severe inflammation and damage to liver, lungs, and kidneys. Cell viability and wound healing assays revealed that ZnO-NPs killed macrophages in a dose-dependent manner, caused severe wounds and inhibited cellular migration by irreversible actin depolymerization and degradation. Reduction in the viability of macrophages was due to the arrest of the cell cycle at the G0/G1 phase, inhibition of superoxide dismutase and catalase and eventually reactive oxygen species. Furthermore, treatment with an antioxidant drug N-acetyl cysteine significantly reduced the ZnO-NP induced genotoxicity bothin vitroandin vivo Altogether, this study gives detailed pathological insights of ZnO-NP that impair cellular functions, thus will enable to arbitrate their biological applications.
authors.affiliation: *School of Biotechnology, Campus-11 and asonawane@kiitbiotech.ac.in.
authors.forename: Rashmirekha
authors.initials: R
authors.lastname: Pati
authors.affiliation: *School of Biotechnology, Campus-11 and.
authors.forename: Ishani
authors.initials: I
authors.lastname: Das
authors.affiliation: *School of Biotechnology, Campus-11 and.
authors.forename: Ranjit Kumar
authors.initials: RK
authors.lastname: Mehta
authors.affiliation: School of Applied Sciences, Campus-3, KIIT University, Bhubaneswar 751024, Orissa, India.
authors.forename: Rojalin
authors.initials: R
authors.lastname: Sahu
authors.affiliation: *School of Biotechnology, Campus-11 and asonawane@kiitbiotech.ac.in.
authors.forename: Avinash
authors.initials: A
authors.lastname: Sonawane
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics*; D000818:Animals; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D043171:Chromosomal Instability / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009153:Mutagens / Q000633:toxicity*; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D015034:Zinc Oxide / Q000737:chemistry / Q000633:toxicity*
chemical_list: D051339:Actin Depolymerizing Factors; D009153:Mutagens; D015034:Zinc Oxide
keywords: DNA damage; autophagy; blood cells; bone marrow cells; chromosomal aberrations; oxidative stress; zinc oxide nanoparticles