title: Weak silica nanomaterial-induced genotoxicity can be explained by indirect DNA damage as shown by the OGG1-modified comet assay and genomic analysis.
abstract: In a previous study, 15-nm silica nanoparticles (NPs) caused small increases in DNA damage in liver as measured in the in vivo comet and micronucleus assays after intravenous administration to rats at their maximum tolerated dose, a worst-case exposure scenario. Histopathological examination supported a particle-induced, tissue damage-mediated inflammatory response. This study used a targeted approach to provide insight into the mode of action (MoA) by examining transcriptional regulation of genes in liver in a time and dose-dependent manner at 1, 2, 4, 8 and 24 h after intravenous administration of 15-nm silica NPs. DNA damage was assessed using the standard comet assay and hOGG1 glycosylase-modified comet assay that also measures oxidative DNA damage. Potassium bromate, an IARC Class 2B carcinogen that specifically operates via an oxidative stress MoA, was used as a positive control for the hOGG1 comet assay and gave a strong signal in its main target organ, the kidney, while showing less activity in liver. Treatment of rats with silica NPs at 50 mg/kg body weight (bw) caused small, statistically insignificant increases in DNA damage in liver measured by the standard comet assay, while a statistically significant increase was observed at 4 h with the hOGG1 comet assay, consistent with a MoA involving reactive oxygen species. Histopathology showed liver damage and neutrophil involvement while genomic analysis and response pattern of key genes involved in inflammation and oxidative stress supported a tissue damage-mediated inflammatory response involving the complement system for removing/phagocytising damaged cells. No changes were observed for histopathology or gene array for the low-dose (5 mg/kg bw) silica NPs. The results of this study confirm our hypothesis that the weak DNA damage observed by silica NPs occurs secondary to inflammation/immune response, indicating that a threshold can be applied in the risk assessment of these materials.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfuhler
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Downs
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Allemang
authors.forename: Yuching
authors.initials: Y
authors.lastname: Shan
authors.affiliation: Present address: AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Crosby
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D020552:Comet Assay; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D045647:DNA Glycosylases; D020869:Gene Expression Profiling; D007249:Inflammation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*
chemical_list: D012822:Silicon Dioxide; D004247:DNA; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human