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Biodistribution of inhaled metal oxide nanoparticles mimicking occupational exposure: a preliminary investigation using enhanced darkfield microscopy.

ABSTRACT: Inhalation exposure to engineered nanomaterials (ENMs) may result in adverse pulmonary and/or systemic health effects. In this study, enhanced darkfield microscopy (EDFM) was used as a novel approach to visualizing industrial metal oxide nanoparticles (NPs) (silica, ceria, or alumina) in multiple tissue types following inhalation in rats mimicking occupational exposures. Advantages of EDFM over electron microscopy (EM) include reduced cost, time, and ease of sample preparation and operation. Following 4-6 hour inhalation exposures at three concentrations (3.5-34.0 mg/m3 ), lungs and secondary organs were harvested at 24 hours or 7 days post-exposure and prepared for brightfield (BF) microscopy and EDFM. NPs were visualized within the lung and associated lymphatic tissues and in major organs of excretion (liver, spleen, kidney). EDFM also revealed NPs within pulmonary blood vessels and localization within specific regions of toxicological relevance in liver and kidney, indicating pathways of excretion. Results demonstrate the utility of EDFM for rapid direct visualization of NPs in various tissue types and suggest the potential for metal oxide NPs to distribute to secondary tissues following inhalation exposure. Confirmation of the composition, distribution, and relative abundance of inhaled NPs will be pursued by combining EDFM with hyperspectral imaging (HSI) and mapping.

SUBMITTER: Guttenberg M

PROVIDER: S-EPMC5291524 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Biodistribution of inhaled metal oxide nanoparticles mimicking occupational exposure: a preliminary investigation using enhanced darkfield microscopy.

Guttenberg Marissa M Bezerra Leonardo L Neu-Baker Nicole M NM Del Pilar Sosa Idelchik María M Elder Alison A Oberdörster Günter G Brenner Sara A SA

Journal of biophotonics 20160816 10

Inhalation exposure to engineered nanomaterials (ENMs) may result in adverse pulmonary and/or systemic health effects. In this study, enhanced darkfield microscopy (EDFM) was used as a novel approach to visualizing industrial metal oxide nanoparticles (NPs) (silica, ceria, or alumina) in multiple tissue types following inhalation in rats mimicking occupational exposures. Advantages of EDFM over electron microscopy (EM) include reduced cost, time, and ease of sample preparation and operation. Fol ...[more]

PMID: 27528427

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Project description:BackgroundCerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation. Therefore, understanding the pharmacokinetic of newly-generated and atmospherically-aged CeO2 nanoparticles is needed to assess the risks to human health.MethodsA novel experimental system was designed to integrate the generation, aging, and inhalation exposure of Sprague Dawley rats to combustion-generated CeO2 nanoparticles (25 and 90 nm bimodal distribution). Aging was done in a chamber representing typical ambient urban air conditions with UV lights. Following a single 4-hour nose-only exposure to freshly emitted or aged CeO2 for 15 min, 24 h, and 7 days, ICP-MS detection of Ce in the blood, lungs, gastrointestinal tract, liver, spleen, kidneys, heart, brain, olfactory bulb, urine, and feces were analyzed with a mass balance approach to gain an overarching understanding of the distribution. A physiologically based pharmacokinetic (PBPK) model that includes mucociliary clearance, phagocytosis, and entry into the systemic circulation by alveolar wall penetration was developed to predict the biodistribution kinetic of the inhaled CeO2 nanoparticles.ResultsCerium was predominantly recovered in the lungs and feces, with extrapulmonary organs contributing less than 4 % to the recovery rate at 24 h post exposure. No significant differences in biodistribution patterns were found between fresh and aged CeO2 nanoparticles. The PBPK model predicted the biodistribution well and identified phagocytizing cells in the pulmonary region accountable for most of the nanoparticles not eliminated by feces.ConclusionsThe biodistribution of fresh and aged CeO2 nanoparticles followed the same patterns, with the highest amounts recovered in the feces and lungs. The slow decrease of nanoparticle concentrations in the lungs can be explained by clearance to the gastrointestinal tract and then to the feces. The PBPK model successfully predicted the kinetic of CeO2 nanoparticles in various organs measured in this study and suggested most of the nanoparticles were captured by phagocytizing cells.

Project description:The use of engineered nanomaterials (ENMs) in foods and consumer products is rising, increasing the potential for unintentional ingestion. While the cytotoxicity of many ENMs has been investigated, less attention has been given to adverse impact on the intestinal barrier integrity. Chronical disruption of gastrointestinal integrity can have far reaching health implications. Using fully differentiated Caco-2 cells, the perturbation of intestinal barrier function and cytotoxicity were investigated for 20 metal, metal oxide, and metal sulfide ENMs. Caco-2 cells were exposed to 50 μg/mL ENMs for 24 hours. ENM formulations were characterized at 0 and 24 hours, and In Vitro Sedimentation, Diffusion and Dosimetry Modeling was applied to calculate the effective dose of exposure during 24 hours. The apparent permeability coefficient (Papp) was determined for fluorescent labeled dextran (3,000 Da) and tight junction integrity was evaluated by immunofluorescence microscopy. Cytotoxicity was investigated by determining lactate dehydrogenase release (LDH) and cell metabolic activity (tetrazolium based MTS) assays. Four ENMs led to significantly increased Papp, (15.8% w/w% Ag-SiO2 nanoparticle (NP), 60 nm CdS NP, 100 nm V2O5 flakes, and 50 nm ZnO NP), while one ENM (20 nm MgO NP) decreased Papp. With the exception of CdS NP, significantly increased Papp was not connected with cell cytotoxicity. The calculated effective dose concentration was not correlated with increased Papp. Our results illustrate that while many metal, metal oxide, and metal sulfide ENMs do not adversely affect monolayer integrity or induce cytotoxicity in differentiated Caco-2 cells, a subset of ENMs may compromise the intestinal integrity. This study demonstrated the use of differentiated Caco-2 monolayer and Papp as an endpoint to identify and prioritize ENMs that should be investigated further. The interaction between ENMs and the intestinal epithelium needs to be evaluated to understand potential intestinal barrier dysfunction and resulting health implications.

Project description:ObjectivesTo characterize contemporary use of inhaled nitric oxide in pediatric acute respiratory failure and to assess relationships between clinical variables and outcomes. We sought to study the relationship of inhaled nitric oxide response to patient characteristics including right ventricular dysfunction and clinician responsiveness to improved oxygenation. We hypothesize that prompt clinician responsiveness to minimize hyperoxia would be associated with improved outcomes.DesignAn observational cohort study.SettingEight sites of the Collaborative Pediatric Critical Care Research Network.PatientsOne hundred fifty-one patients who received inhaled nitric oxide for a primary respiratory indication.Measurements and main resultsClinical data were abstracted from the medical record beginning at inhaled nitric oxide initiation and continuing until the earliest of 28 days, ICU discharge, or death. Ventilator-free days, oxygenation index, and Functional Status Scale were calculated. Echocardiographic reports were abstracted assessing for pulmonary hypertension, right ventricular dysfunction, and other cardiovascular parameters. Clinician responsiveness to improved oxygenation was determined. One hundred thirty patients (86%) who received inhaled nitric oxide had improved oxygenation by 24 hours. PICU mortality was 29.8%, while a new morbidity was identified in 19.8% of survivors. Among patients who had echocardiograms, 27.9% had evidence of pulmonary hypertension, 23.1% had right ventricular systolic dysfunction, and 22.1% had an atrial communication. Moderate or severe right ventricular dysfunction was associated with higher mortality. Clinicians responded to an improvement in oxygenation by decreasing FIO2 to less than 0.6 within 24 hours in 71% of patients. Timely clinician responsiveness to improved oxygenation with inhaled nitric oxide was associated with more ventilator-free days but not less cardiac arrests, mortality, or additional morbidity.ConclusionsClinician responsiveness to improved oxygenation was associated with less ventilator days. Algorithms to standardize ventilator management may improve signal to noise ratios in future trials enabling better assessment of the effect of inhaled nitric oxide on patient outcomes. Additionally, confining studies to more selective patient populations such as those with right ventricular dysfunction may be required.

Dataset Information

Biodistribution of inhaled metal oxide nanoparticles mimicking occupational exposure: a preliminary investigation using enhanced darkfield microscopy.

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Biodistribution of inhaled metal oxide nanoparticles mimicking occupational exposure: a preliminary investigation using enhanced darkfield microscopy.

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