The use of cerium compounds as diesel fuel catalyst results in the emission of cerium oxide nanoparticles (CeO2) in the exhaust. This study characterized the potential effects of CeO2 exposure on lung toxicity. Male Sprague Dawley rats were exposed to CeO2 by a single intratracheal instillation at 0.15, 0.5, 1, 3.5 or 7 mg/kg body weight. At 1 day after exposure, CeO2 significantly reduced NO production, but increased IL-12 production, by alveolar macrophages (AM) in response to ex vivo lipopolysacchride (LPS) challenge, and caused AM apoptosis, through activation of caspases 9 and 3. CeO2 exposure markedly increased suppressor of cytokine signaling-1 at 1-day and elevated arginase-1 at 28-day post exposure in lung cells, while osteopontin was significantly elevated in lung tissue at both time points. CeO2 induced inflammation, cytotoxicity, air/blood barrier damage, and phospholipidosis with enlarged AM. Thus, CeO2 induced lung inflammation and injury in lungs which may lead to fibrosis.

Nanoscale CeO2 is increasingly used for industrial and commercial applications, including catalysis, UV-shielding, and as an additive in various nanocomposites. Because of its increasing potential for consumer and occupational exposures, a comprehensive toxicological characterization of this nanomaterial is needed. Preliminary results from intratracheal instillation studies in rats point to cytoxicity and inflammation, though these studies may not accurately use realistic nanoscale exposure profiles. In contrast, published in vitro cellular studies have reported limited toxicological outcomes for the case of nano-ceria. Here, we present an integrative study evaluating the toxicity of nanoscale CeO2 both in vitro, using the A549 lung epithelial cell line, and in vivo using an intact rat model. Realistic nano-ceria exposure atmospheres were generated using the Harvard Versatile Engineered Nanomaterial Generation System (VENGES), and rats were exposed via inhalation. Finally, the use of a nanothin amorphous SiO2 encapsulation coating as a means of mitigating CeO2 toxicity was assessed. Results from the inhalation experiments show lung injury and inflammation with increased PMN and LDH levels in the bronchoalveolar lavage fluid of the CeO2 exposed rats. Moreover, exposure to SiO2-coated CeO2 did not induce any pulmonary toxicity to the animals, representing clear evidence for the safe by design SiO2-encapsualtion concept.

Cerium compounds have been used as a diesel engine catalyst to lower the mass of diesel exhaust particles, but are emitted as cerium oxide (CeO(2)) nanoparticles in the diesel exhaust. In a previous study, we have demonstrated a wide range of CeO(2)-induced lung responses including sustained pulmonary inflammation and cellular signaling that could lead to pulmonary fibrosis. In this study, we investigated the fibrogenic responses induced by CeO(2) in a rat model at various time points up to 84 days post-exposure. Male Sprague Dawley rats were exposed to CeO(2) by a single intratracheal instillation. Alveolar macrophages (AM) were isolated by bronchial alveolar lavage (BAL). AM-mediated cellular responses, osteopontin (OPN) and transform growth factor (TGF)-β1 in the fibrotic process were investigated. The results showed that CeO(2) exposure significantly increased fibrotic cytokine TGF-β1 and OPN production by AM above controls. The collagen degradation enzymes, matrix metalloproteinase (MMP)-2 and -9 and the tissue inhibitor of MMP were markedly increased in the BAL fluid at 1 day- and subsequently declined at 28 days after exposure, but remained much higher than the controls. CeO(2) induced elevated phospholipids in BAL fluid and increased hydroxyproline content in lung tissue in a dose- and time-dependent manner. Immunohistochemical analysis showed MMP-2, MMP-9 and MMP-10 expressions in fibrotic regions. Morphological analysis noted increased collagen fibers in the lungs exposed to a single dose of 3.5mg/kg CeO(2) and euthanized at 28 days post-exposure. Collectively, our studies show that CeO(2) induced fibrotic lung injury in rats, suggesting it may cause potential health effects.

Exposure to diesel exhaust particles (DEP) is an environmental and occupational health concern. This review examines the cellular actions of the organic and the particulate components of DEP in the development of various lung diseases. Both the organic and the particulate components cause oxidant lung injury. The particulate component is known to induce alveolar epithelial damage, alter thiol levels in alveolar macrophages (AM) and lymphocytes, and activate AM in the production of reactive oxygen species (ROS) and pro-inflammatory cytokines. The organic component, on the other hand, is shown to generate intracellular ROS, leading to a variety of cellular responses including apoptosis. There are a number of differences between the biological actions exerted by these two components. The organic component is responsible for DEP induction of cytochrome P450 family 1 enzymes that are critical to the polycyclic aromatic hydrocarbons (PAH) and nitro-PAH metabolism in the lung as well as in the liver. The particulate component, on the other hand, causes a sustained down-regulation of CYP2B1 in the rat lung. The significance of this effect on pulmonary metabolism of xenobiotics and endobiotics remains to be seen, but may prove to be an important factor governing the interplay of the pulmonary metabolic and inflammatory systems. Long-term exposures to various particles including DEP, carbon black (CB), TiO2, and washed DEP devoid of the organic content, have been shown to produce similar tumorigenic responses in rodents. There is a lack of correlation between tumor development and DEP chemical-derived DNA adduct formation. But the organic component has been shown to generate ROS that produce 8-hydroxydeoxyguanosine (8-OHdG) in cell culture. The organic, but not the particulate, component of DEP suppresses the production of pro-inflammatory cytokines by AM and the development of Th1 cell-mediated immunity. The mechanism for this effect is not yet clear, but may involve the induction of heme oxygenase-1 (HO-1), a cellular genetic response to oxidative stress. Both the organic and the particulate components of DEP enhance respiratory allergic sensitization. Part of the DEP effects may be due to a depletion of glutathione in lymphocytes. The organic component, which is shown to induce IL-4 and IL-10 productions, may skew the immunity toward Th2 response, whereas the particulate component may stimulate both the Th1 and Th2 responses. In conclusion, the literature shows that the particulate and organic components of DEP exhibit different biological actions but both involve the induction of cellular oxidative stress. Together, these effects inhibit cell-mediated immunity toward infectious agents, exacerbate respiratory allergy, cause DNA damage, and under long-term exposure, induce the development of lung tumors.

Background: Cerium oxide (CeO 2 ) nanoparticles have been posited to have both beneficial and toxic effects on biological systems. Herein, we examine if a single intratracheal instillation of CeO 2 nanoparticles is associated with systemic toxicity in male Sprague-Dawley rats. Methods and results:Compared with control animals, CeO 2 nanoparticle exposure was associated with increased liver ceria levels, elevations in serum alanine transaminase levels, reduced albumin levels, a diminished sodium-potassium ratio, and decreased serum triglyceride levels (P , 0.05). Consistent with these data, rats exposed to CeO 2 nanoparticles also exhibited reductions in liver weight (P , 0.05) and dose-dependent hydropic degeneration, hepatocyte enlargement, sinusoidal dilatation, and accumulation of granular material. No histopathological alterations were observed in the kidney, spleen, and heart. Analysis of serum biomarkers suggested an elevation of acute phase reactants and markers of hepatocyte injury in the rats exposed to CeO 2 nanoparticles. Conclusion: Taken together, these data suggest that intratracheal instillation of CeO 2 nanoparticles can result in liver damage.