title: Acute and long-term in vitro effects of zinc oxide nanoparticles.
abstract: Since most of the toxic studies of zinc oxide nanoparticles (ZnO NPs) focused on acute and high-dose exposure conditions, the aim of the present study was to fill the existing knowledge gap of long-term effects of ZnO NPs at sub-toxic doses. To overcome this point, we have evaluated the toxic, genotoxic, and carcinogenic effects of ZnO NPs under long-term treatments (12 weeks), using a sub-toxic dose (1 µg/mL) according to acute 48-h exposure. Preliminarily, oxidative stress and genotoxic/oxidative DNA damage were determined under acute exposure and high-dose conditions. To determine the role of oxidative DNA damage, a wild-type mouse embryonic fibroblast (MEF Ogg1 (+/+)) and its isogenic 8-oxo-guanine DNA glycosylase 1 (Ogg1) knockout partner (MEF Ogg1 (-/-)) cell lines were used. Although short-term exposure (24-h) experiments demonstrated that ZnO NPs were able to induce ROS, genotoxicity, and oxidative DNA damage in both cell lines, no effects were obtained under long-term exposure scenario. Thus, 1 µg/mL exposure over 12 weeks was unable to induce genotoxicity as well as cellular transformation in both cell types, as indicated by the lack of observed morphological cell changes, variations in the secretion of matrix metalloproteinases, and anchorage-independent cell growth ability, regarded as cancer-like phenotypic hallmarks. Our results indicate that short-term effects of ZnO NP exposure are not replicated under long-term and sub-toxic dose conditions. All together, the lack of genotoxic/carcinogenic effects after chronic treatments seem to indicate a reduced risk associated with ZnO NP exposure.
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Spain.
authors.forename: Balasubramanyam
authors.initials: B
authors.lastname: Annangi
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rubio
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Spain.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Alaraby
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bach
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Spain. ricard.marcos@uab.es.|CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain. ricard.marcos@uab.es.
authors.forename: Ricard
authors.initials: R
authors.lastname: Marcos
authors.affiliation: Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193, Cerdanyola del Vallès, Spain. alba.hernandez@uab.es.|CIBER Epidemiología y Salud Pública, ISCIII, Madrid, Spain. alba.hernandez@uab.es.
authors.forename: Alba
authors.initials: A
authors.lastname: Hernández
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D002478:Cells, Cultured; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053768:Metal Nanoparticles / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D018570:Risk Assessment; D013997:Time Factors; D015034:Zinc Oxide / Q000633:toxicity*
chemical_list: D017382:Reactive Oxygen Species; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D015034:Zinc Oxide
keywords: Genotoxic/carcinogenic effects; Long-term exposures; Zinc oxide nanoparticles