title: Alteration of hepatic structure and oxidative stress induced by intravenous nanoceria.
abstract: Beyond the traditional use of ceria as an abrasive, the scope of nanoceria applications now extends into fuel cell manufacturing, diesel fuel additives, and for therapeutic intervention as a putative antioxidant. However, the biological effects of nanoceria exposure have yet to be fully defined, which gave us the impetus to examine its systemic biodistribution and biological responses. An extensively characterized nanoceria (5 nm) dispersion was vascularly infused into rats, which were terminated 1 h, 20 h or 30 days later. Light and electron microscopic tissue characterization was conducted and hepatic oxidative stress parameters determined. We observed acute ceria nanoparticle sequestration by Kupffer cells with subsequent bioretention in parenchymal cells as well. The internalized ceria nanoparticles appeared as spherical agglomerates of varying dimension without specific organelle penetration. In hepatocytes, the agglomerated nanoceria frequently localized to the plasma membrane facing bile canaliculi. Hepatic stellate cells also sequestered nanoceria. Within the sinusoids, sustained nanoceria bioretention was associated with granuloma formations comprised of Kupffer cells and intermingling CD3⁺ T cells. A statistically significant elevation of serum aspartate aminotransferase (AST) level was seen at 1 and 20 h, but subsided by 30 days after ceria administration. Further, elevated apoptosis was observed on day 30. These findings, together with increased hepatic protein carbonyl levels on day 30, indicate ceria-induced hepatic injury and oxidative stress, respectively. Such observations suggest a single vascular infusion of nanoceria can lead to persistent hepatic retention of particles with possible implications for occupational and therapeutic exposures.
authors.affiliation: Dept of Anatomical Sciences & Neurobiology, University of Louisville, Louisville, Kentucky, USA. mttsen01@louisville.edu
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tseng
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Lu
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Duan
authors.forename: Sarita S
authors.initials: SS
authors.lastname: Hardas
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.forename: Jason M
authors.initials: JM
authors.lastname: Unrine
authors.forename: Uschi
authors.initials: U
authors.lastname: Graham
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: Eric A
authors.initials: EA
authors.lastname: Grulke
authors.forename: Robert A
authors.initials: RA
authors.lastname: Yokel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002374:Catalase / Q000378:metabolism; D002563:Cerium / Q000737:chemistry / Q000633:toxicity*; D005980:Glutathione Reductase / Q000378:metabolism; D006099:Granuloma / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D002563:Cerium; C002744:3-nitrotyrosine; D014443:Tyrosine; C030583:ceric oxide; D002374:Catalase; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D001219:Aspartate Aminotransferases