Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-8 (of 8 Records) |
Query Trace: Graham UM [original query] |
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Macrophage polarization status impacts nanoceria cellular distribution but not its biotransformation or ferritin effects
Graham UM , Dozier AK , Feola DJ , Tseng MT , Yokel RA . Nanomaterials (Basel) 2023 13 (16) The innate immune system is the first line of defense against external threats through the initiation and regulation of inflammation. Macrophage differentiation into functional phenotypes influences the fate of nanomaterials taken up by these immune cells. High-resolution electron microscopy was used to investigate the uptake, distribution, and biotransformation of nanoceria in human and murine M1 and M2 macrophages in unprecedented detail. We found that M1 and M2 macrophages internalize nanoceria differently. M1-type macrophages predominantly sequester nanoceria near the plasma membrane, whereas nanoceria are more uniformly distributed throughout M2 macrophage cytoplasm. In contrast, both macrophage phenotypes show identical nanoceria biotransformation to cerium phosphate nanoneedles and simultaneous nanoceria with ferritin co-precipitation within the cells. Ferritin biomineralization is a direct response to nanoparticle uptake inside both macrophage phenotypes. We also found that the same ferritin biomineralization mechanism occurs after the uptake of Ce-ions into polarized macrophages and into unpolarized human monocytes and murine RAW 264.7 cells. These findings emphasize the need for evaluating ferritin biomineralization in studies that involve the internalization of nano objects, ranging from particles to viruses to biomolecules, to gain greater mechanistic insights into the overall immune responses to nano objects. |
Nanoceria distribution and effects are mouse-strain dependent
Yokel RA , Tseng MT , Butterfield DA , Hancock ML , Grulke EA , Unrine JM , Stromberg AJ , Dozier AK , Graham UM . Nanotoxicology 2020 14 (6) 1-20 Prior studies showed nanoparticle clearance was different in C57BL/6 versus BALB/c mice, strains prone to Th1 and Th2 immune responses, respectively. Objective: Assess nanoceria (cerium oxide, CeO2 nanoparticle) uptake time course and organ distribution, cellular and oxidative stress, and bioprocessing as a function of mouse strain. Methods: C57BL/6 and BALB/c female mice were i.p. injected with 10 mg/kg nanoceria or vehicle and terminated 0.5 to 24 h later. Organs were collected for cerium analysis; light and electron microscopy with elemental mapping; and protein carbonyl, IL-1beta, and caspase-1 determination. Results: Peripheral organ cerium significantly increased, generally more in C57BL/6 mice. Caspase-1 was significantly elevated in the liver at 6 h, to a greater extent in BALB/c mice, suggesting inflammasome pathway activation. Light microscopy revealed greater liver vacuolation in C57BL/6 mice and a nanoceria-induced decrease in BALB/c but not C57BL/6 mice vacuolation. Nanoceria increased spleen lymphoid white pulp cell density in BALB/c but not C57BL/6 mice. Electron microscopy showed intracellular nanoceria particles bioprocessed to form crystalline cerium phosphate nanoneedles. Ferritin accumulation was greatly increased proximal to the nanoceria, forming core-shell-like structures in C57BL/6 but even distribution in BALB/c mice. Conclusions: BALB/c mice were more responsive to nanoceria-induced effects, e.g. liver caspase-1 activation, reduced liver vacuolation, and increased spleen cell density. Nanoceria uptake, initiation of bioprocessing, and crystalline cerium phosphate nanoneedle formation were rapid. Ferritin greatly increased with a macrophage phenotype-dependent distribution. Further study will be needed to understand the mechanisms underlying the observed differences. |
Tissue specific fate of nanomaterials by advanced analytical imaging techniques - a review
Graham UM , Dozier AK , Oberdörster G , Yokel RA , Molina R , Brain JD , Pinto JM , Weuve J , Bennett DA . Chem Res Toxicol 2020 33 (5) 1145-1162 A variety of imaging and analytical methods have been developed to study nanoparticles in cells. Each has its benefits, limitations, and varying degrees of expense and difficulties in implementation. High-resolution analytical scanning transmission electron microscopy (HRSTEM) has the unique ability to image local cellular environments adjacent to a nanoparticle at near atomic resolution and apply analytical tools to these environments such as energy dispersive spectroscopy and electron energy loss spectroscopy. These tools can be used to analyze particle location, translocation and potential reformation, ion dispersion, and in vivo synthesis of second-generation nanoparticles. Such analyses can provide in depth understanding of tissue-particle interactions and effects that are caused by the environmental "invader" nanoparticles. Analytical imaging can also distinguish phases that form due to the transformation of "invader" nanoparticles in contrast to those that are triggered by a response mechanism, including the commonly observed iron biomineralization in the form of ferritin nanoparticles. The analyses can distinguish ion species, crystal phases, and valence of parent nanoparticles and reformed or in vivo synthesized phases throughout the tissue. This article will briefly review the plethora of methods that have been developed over the last 20 years with an emphasis on the state-of-the-art techniques used to image and analyze nanoparticles in cells and highlight the sample preparation necessary for biological thin section observation in a HRSTEM. Specific applications that provide visual and chemical mapping of the local cellular environments surrounding parent nanoparticles and second-generation phases are demonstrated, which will help to identify novel nanoparticle-produced adverse effects and their associated mechanisms. |
Predicting dissolution and transformation of inhaled nanoparticles in the lung using abiotic flow cells: The case of barium sulfate
Keller JG , Graham UM , Koltermann-Jully J , Gelein R , Ma-Hock L , Landsiedel R , Wiemann M , Oberdorster G , Elder A , Wohlleben W . Sci Rep 2020 10 (1) 458-458 Barium sulfate (BaSO(4)) was considered to be poorly-soluble and of low toxicity, but BaSO(4) NM-220 showed a surprisingly short retention after intratracheal instillation in rat lungs, and incorporation of Ba within the bones. Here we show that static abiotic dissolution cannot rationalize this result, whereas two dynamic abiotic dissolution systems (one flow-through and one flow-by) indicated 50% dissolution after 5 to 6 days at non-saturating conditions regardless of flow orientation, which is close to the in vivo half-time of 9.6 days. Non-equilibrium conditions were thus essential to simulate in vivo biodissolution. Instead of shrinking from 32 nm to 23 nm (to match the mass loss to ions), TEM scans of particles retrieved from flow-cells showed an increase to 40 nm. Such transformation suggested either material transport through interfacial contact or Ostwald ripening at super-saturating conditions and was also observed in vivo inside macrophages by high-resolution TEM following 12 months inhalation exposure. The abiotic flow cells thus adequately predicted the overall pulmonary biopersistence of the particles that was mediated by non-equilibrium dissolution and recrystallization. The present methodology for dissolution and transformation fills a high priority gap in nanomaterial hazard assessment and is proposed for the implementation of grouping and read-across by dissolution rates. |
Carboxylic acids accelerate acidic environment-mediated nanoceria dissolution
Yokel RA , Hancock ML , Grulke EA , Unrine JM , Dozier AK , Graham UM . Nanotoxicology 2019 13 (4) 1-21 Ligands that accelerate nanoceria dissolution may greatly affect its fate and effects. This project assessed the carboxylic acid contribution to nanoceria dissolution in aqueous, acidic environments. Nanoceria has commercial and potential therapeutic and energy storage applications. It biotransforms in vivo. Citric acid stabilizes nanoceria during synthesis and in aqueous dispersions. In this study, citrate-stabilized nanoceria dispersions ( approximately 4 nm average primary particle size) were loaded into dialysis cassettes whose membranes passed cerium salts but not nanoceria particles. The cassettes were immersed in iso-osmotic baths containing carboxylic acids at pH 4.5 and 37 degrees C, or other select agents. Cerium atom material balances were conducted for the cassette and bath by sampling of each chamber and cerium quantitation by ICP-MS. Samples were collected from the cassette for high-resolution transmission electron microscopy observation of nanoceria size. In carboxylic acid solutions, nanoceria dissolution increased bath cerium concentration to >96% of the cerium introduced as nanoceria into the cassette and decreased nanoceria primary particle size in the cassette. In solutions of citric, malic, and lactic acids and the ammonium ion approximately 15 nm, ceria agglomerates persisted. In solutions of other carboxylic acids, some select nanoceria agglomerates grew to approximately 1 micron. In carboxylic acid solutions, dissolution half-lives were 800-4000 h; in water and horseradish peroxidase they were >/=55,000 h. Extending these findings to in vivo and environmental systems, one expects acidic environments containing carboxylic acids to degrade nanoceria by dissolution; two examples would be phagolysosomes and in the plant rhizosphere. |
Analytical high-resolution electron microscopy reveals organ-specific nanoceria bioprocessing
Graham UM , Yokel RA , Dozier AK , Drummy L , Mahalingam K , Tseng MT , Birch E , Fernback J . Toxicol Pathol 2018 46 (1) 47-61 This is the first utilization of advanced analytical electron microscopy methods, including high-resolution transmission electron microscopy, high-angle annular dark field scanning transmission electron microscopy, electron energy loss spectroscopy, and energy-dispersive X-ray spectroscopy mapping to characterize the organ-specific bioprocessing of a relatively inert nanomaterial (nanoceria). Liver and spleen samples from rats given a single intravenous infusion of nanoceria were obtained after prolonged (90 days) in vivo exposure. These advanced analytical electron microscopy methods were applied to elucidate the organ-specific cellular and subcellular fate of nanoceria after its uptake. Nanoceria is bioprocessed differently in the spleen than in the liver. |
From dose to response: In vivo nanoparticle processing and potential toxicity
Graham UM , Jacobs G , Yokel RA , Davis BH , Dozier AK , Birch ME , Tseng MT , Oberdorster G , Elder A , DeLouise L . Adv Exp Med Biol 2017 947 71-100 Adverse human health impacts due to occupational and environmental exposures to manufactured nanoparticles are of concern and pose a potential threat to the continued industrial use and integration of nanomaterials into commercial products. This chapter addresses the inter-relationship between dose and response and will elucidate on how the dynamic chemical and physical transformation and breakdown of the nanoparticles at the cellular and subcellular levels can lead to the in vivo formation of new reaction products. The dose-response relationship is complicated by the continuous physicochemical transformations in the nanoparticles induced by the dynamics of the biological system, where dose, bio-processing, and response are related in a non-linear manner. Nanoscale alterations are monitored using high-resolution imaging combined with in situ elemental analysis and emphasis is placed on the importance of the precision of characterization. The result is an in-depth understanding of the starting particles, the particle transformation in a biological environment, and the physiological response. |
In vivo processing of ceria nanoparticles inside liver: impact on free-radical scavenging activity and oxidative stress
Graham UM , Tseng MT , Jasinski JB , Yokel RA , Unrine JM , Davis BH , Dozier AK , Hardas SS , Sultana R , Grulke EA , Butterfield DA . Chempluschem 2014 79 (8) 1083-1088 The cytotoxicity of ceria ultimately lies in its electronic structure, which is defined by the crystal structure, composition, and size. Despite previous studies focused on ceria uptake, distribution, biopersistance, and cellular effects, little is known about its chemical and structural stability and solubility once sequestered inside the liver. Mechanisms will be presented that elucidate the in vivo transformation in the liver. In vivo processed ceria reveals a particle-size effect towards the formation of ultrafines, which represent a second generation of ceria. A measurable change in the valence reduction of the second-generation ceria can be linked to an increased free-radical scavenging potential. The in vivo processing of the ceria nanoparticles in the liver occurs in temporal relation to the brain cellular and protein clearance responses that stem from the ceria uptake. This information is critical to establish a possible link between cellular processes and the observed in vivo transformation of ceria. The temporal linkage between the reversal of the pro-oxidant effect (brain) and ceria transformation (liver) suggests a cause-effect relationship. |
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