In Vivo Processing of Ceria Nanoparticles inside Liver: Impact on Free‐Radical Scavenging Activity and Oxidative Stress

Graham, Uschi M.; Tseng, Michael T.; Jasiński, Jacek B.; Yokel, Robert A.; Unrine, Jason M.; Davis, Burtron H.; Dozier, Alan; Hardas, Sarita S.; Sultana, Rukhsana; Grulke, Eric A.; Butterfield, D. Allan

doi:10.1002/cplu.201402080

Cited by 73 publications

(104 citation statements)

References 45 publications

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“…2). Inflammatory responses have been previously shown to activate abundant ferritin formation in localized regions with invader nanoparticles [3]. The current study shows for the first time that the same process occurs after in vivo delivery of ions, followed by their transport, and precipitation.…”

supporting

confidence: 64%

In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl₃: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment

et al. 2017

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We demonstrate the in vivo formation of nano-particulate Ce-containing structures in lungs instilled with 5 mg/kg CeCl3 using high resolution electron microscopy (HRTEM), energy loss spectroscopy (EELS), and elemental mapping (EDS). The observed high lung retention of Ce after instillation of CeCl3 (75-92% retained at 28 days) is unexpected since metal ions are usually readily transported across the air-blood barrier. The binding of cerium ions to lung constituents has been suggested [1], and the formation of cerium phosphate has been shown previously, but without discussions on the mechanisms involved in nanoparticle nucleation and growth [2]. Determining the form of Ce after lung exposure to CeCl3 has been challenging due to the difficulties in distinguishing ions from particulate forms when using radioactivity or ICP-MS. We have identified cerium nanoparticles at the sub-cellular level in lung macrophages after CeCl3 instillation. This observation provides insights on the cell structures and components that will help distinguish which cellular areas are the sites of in vivo nanoparticle formation.Lung tissue samples were fixed by vascular perfusion with 2.5% glutaraldehyde, 2% paraformaldehyde in 0.1M HEPES buffer. The samples were processed for electron microscopy at 2 hours, 7 days and 4 weeks post-instillation. High-resolution imaging revealed that nanoparticles had formed at all of the selected time-points and were located in lysosomal regions, along membrane surfaces and inside mitochondria. The nanoparticles formed in a narrow particle size range (~1-5 nm) and were bundled together in 3D-agglomerates up to several hundred nm (Fig. 1a). Individual nanoparticles appear self-aligned into rodshaped structures or needles that reach up to 10 nm in length and 2-5 nm in width, with some structures arranged in a spider-like form (Fig. 1b). The typical crystalline structures of individual ultra-fine nanoparticles are shown in Fig. 1c. EELS analyses demonstrate co-localization of Ce and P for individual nanocrystals (Fig. 2). The in vivo nucleation and growth of cerium phosphate nanoparticles in the observed large agglomerates are demonstrated by the EDS elemental maps obtained in the STEM mode (Fig. 2). EDS maps and corresponding spectra indicate that cerium ions formed cerium phosphate nanoparticles. Furthermore, the elemental map also reveals the presence of abundant Fe, which may correspond to the ultrafine ferritin nanoparticles (~5nm) that formed in the vicinity of the cerium phosphate nanoparticles (Fig. 2). Inflammatory responses have been previously shown to activate abundant ferritin formation in localized regions with invader nanoparticles [3]. The current study shows for the first time that the same process occurs after in vivo delivery of ions, followed by their transport, and precipitation.

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confidence: 64%

In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl₃: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment

et al. 2017

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“…The Cd core of the QDs is often toxic-this has to be taken into account in the interpretation of QD bio-distribution and NM-mediated effects (Sanwlani et al 2014, Silva et al 2014, Zhan and Tang 2014. Finally, Ce NMs are distributed much like insoluble NMs, but it has been demonstrated that they are oxidised and re-crystallised as oxidised NMs in the liver (Graham et al 2014). Therefore, it is important to understand the nature of NMs and distinguish between material types (virtually insoluble, slowly and rapidly soluble NMs) in order to gain a better understanding of their ability to translocate, bio-persist and induce of toxicity in secondary organs (Table 4).…”

Section: Discussionmentioning

confidence: 96%

Nanomaterial translocation–the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs–a review

Kermanizadeh

Balharry

Wallin

et al. 2015

Critical Reviews in Toxicology

141

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Engineered nanomaterials (NMs) offer great technological advantages but their risks to human health are still not fully understood. An increasing body of evidence suggests that some NMs are capable of distributing from the site of exposure to a number of secondary organs. The research into the toxicity posed by the NMs in these secondary organs is expanding due to the realisation that some materials may reach and accumulate in these target sites. The translocation to secondary organs includes, but is not limited to, the hepatic, central nervous, cardiovascular and renal systems. Current data indicates that pulmonary exposure is associated with low (inhalation route-0.00001-1% of total applied dose-24 h) translocation of virtually insoluble NMs such as iridium, carbon black, gold and polystyrene, while slightly higher translocation has been observed for NMs with either slow (e.g., silver, cerium dioxide and quantum dots) or fast (e.g., zinc oxide) solubility. The translocation of NMs following intratracheal, intranasal and pharyngeal aspiration is higher (up to 10% of administered dose), however the relevance of these routes for risk assessment is questionable. Uptake of the materials from the gastrointestinal tract seems to follow the same pattern as inhalation translocation, whereas the dermal uptake of NMs is generally reported to be low. The toxicological effects in secondary organs include oxidative stress, inflammation, cytotoxicity and dysfunction of cellular and physiological processes. For toxicological and risk evaluation, further information on the toxicokinetics and persistence of NMs is crucial. The overall aim of this review is to outline the data currently available in the literature on the biokinetics, accumulation, toxicity and eventual fate of NMs in order to assess the potential risks posed by NMs to secondary organs.

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“…Clouds of 1 to 3 nm, (111) and (200) faced, crystalline ceria near the partially biodegraded nanoceria were seen, suggesting a dissolution-precipitation process. EELS showed increased surface Ce 3+ consistent with ultrafine nanoceria particles, suggesting greater anti-oxidant potential 45 . These observations suggest nanoceria bioprocessing to a more stable, potentially more beneficial, nanoceria form.…”

Section: Systemic Nanoceria Exposurementioning

confidence: 91%

The yin: an adverse health perspective of nanoceria: uptake, distribution, accumulation, and mechanisms of its toxicity

Yokel

Hussain

Garantziotis

et al. 2014

Environ. Sci.: Nano

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111

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This critical review evolved from a SNO Special Workshop on Nanoceria panel presentation addressing the toxicological risks of nanoceria: accumulation, target organs, and issues of clearance; how exposure dose/concentration, exposure route, and experimental preparation/model influence the different reported effects of nanoceria; and how can safer by design concepts be applied to nanoceria? It focuses on the most relevant routes of human nanoceria exposure and uptake, disposition, persistence, and resultant adverse effects. The pulmonary, oral, dermal, and topical ocular exposure routes are addressed as well as the intravenous route, as the latter provides a reference for the pharmacokinetic fate of nanoceria once introduced into blood. Nanoceria reaching the blood is primarily distributed to mononuclear phagocytic system organs. Available data suggest nanoceria’s distribution is not greatly affected by dose, shape, or dosing schedule. Significant attention has been paid to the inhalation exposure route. Nanoceria distribution from the lung to the rest of the body is less than 1% of the deposited dose, and from the gastrointestinal tract even less. Intracellular nanoceria and organ burdens persist for at least months, suggesting very slow clearance rates. The acute toxicity of nanoceria is very low. However, large/accumulated doses produce granuloma in the lung and liver, and fibrosis in the lung. Toxicity, including genotoxicity, increases with exposure time; the effects disappear slowly, possibly due to nanoceria’s biopersistence. Nanoceria may exert toxicity through oxidative stress. Adverse effects seen at sites distal to exposure may be due to nanoceria translocation or released biomolecules. An example is elevated oxidative stress indicators in the brain, in the absence of appreciable brain nanoceria. Nanoceria may change its nature in biological environments and cause changes in biological molecules. Increased toxicity has been related to greater surface Ce3+, which becomes more relevant as particle size decreases and the ratio of surface area to volume increases. Given its biopersistence and resulting increased toxicity with time, there is a risk that long-term exposure to low nanoceria levels may eventually lead to adverse health effects. This critical review provides recommendations for research to resolve some of the many unknowns of nanoceria’s fate and adverse effects.

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In Vivo Processing of Ceria Nanoparticles inside Liver: Impact on Free‐Radical Scavenging Activity and Oxidative Stress

Cited by 73 publications

References 45 publications

In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl₃: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment

In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl₃: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment

Nanomaterial translocation–the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs–a review

The yin: an adverse health perspective of nanoceria: uptake, distribution, accumulation, and mechanisms of its toxicity

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In Vivo Processing of Ceria Nanoparticles inside Liver: Impact on Free‐Radical Scavenging Activity and Oxidative Stress

Cited by 73 publications

References 45 publications

In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl3: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment

In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl3: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment

Nanomaterial translocation–the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs–a review

The yin: an adverse health perspective of nanoceria: uptake, distribution, accumulation, and mechanisms of its toxicity

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Product

Resources

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In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl₃: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment

In vivo formation of Ce-phosphate Nanoparticles following Intratracheal Instillation of CeCl₃: Subcellular sites, Nanostructures, Precipitation Mechanisms and Nanoparticle 3D-Alignment