Last data update: Nov 11, 2024. (Total: 48109 publications since 2009)
Records 1-28 (of 28 Records) |
Query Trace: Nurkiewicz T[original query] |
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Face mask fit modifications that improve source control performance (preprint)
Blachere FM , Lemons AR , Coyle JP , Derk RC , Lindsley WG , Beezhold DH , Woodfork K , Duling MG , Boutin B , Boots T , Harris JR , Nurkiewicz T , Noti JD . medRxiv 2021 2021.09.16.21263642 BACKGROUND During the COVID-19 pandemic, face masks are used as source control devices to reduce the expulsion of respiratory aerosols from infected people. Modifications such as mask braces, earloop straps, knotting and tucking, and double masking have been proposed to improve mask fit. However, the data on source control are limited.METHODS The effectiveness of mask fit modifications was determined by conducting fit tests on human subjects and simulator manikins and by performing simulated coughs and exhalations using a source control measurement system.RESULTS Medical masks without modification blocked ≥56% of cough aerosols and ≥42% of exhaled aerosols. Modifying fit by crossing the earloops or placing a bracket under the mask did not increase performance, while using earloop toggles, an earloop strap, and knotting and tucking the mask increased performance. The most effective modifications for improving source control performance were double masking and using a mask brace. Placing a cloth mask over a medical mask blocked ≥85% of cough aerosols and ≥91% of exhaled aerosols. Placing a brace over a medical mask blocked ≥95% of cough aerosols and ≥99% of exhaled aerosols.CONCLUSION Fit modifications can greatly improve the performance of face masks as source control devices for respiratory aerosols.Competing Interest StatementThe authors have declared no competing interest.Funding StatementResearch was supported by the following sources: Centers for Disease Control and Prevention, National Institutes of Health R01 ES015022 (TRN) and WV-CTSI U54 GM104942-05.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:WVU Protocol #: 2009119037All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesData is available from research personnel upon request. |
A comparison of performance metrics for cloth face masks as source control devices for simulated cough and exhalation aerosols (preprint)
Lindsley WG , Blachere FM , Beezhold DH , Law BF , Derk RC , Hettick JM , Woodfork K , Goldsmith WT , Harris JR , Duling MG , Boutin B , Nurkiewicz T , Noti JD . medRxiv 2021 Universal mask wearing is recommended by the Centers for Disease Control and Prevention to help control the spread of COVID-19. Masks reduce the expulsion of respiratory aerosols (called source control) and offer some protection to the wearer. However, masks vary greatly in their designs and construction materials, and it is not clear which are most effective. Our study tested 15 reusable cloth masks (which included face masks, neck gaiters, and bandanas), two medical masks, and two N95 filtering facepiece respirators as source control devices for aerosols ≤ 7 µm produced during simulated coughing and exhalation. These measurements were compared with the mask filtration efficiencies, airflow resistances, and fit factors. The source control collection efficiencies for the cloth masks ranged from 17% to 71% for coughing and 35% to 66% for exhalation. The filtration efficiencies of the cloth masks ranged from 1.4% to 98%, while the fit factors were 1.3 to 7.4 on an elastomeric manikin headform and 1.0 to 4.0 on human test subjects. The correlation coefficients between the source control efficacies and the other performance metrics ranged from 0.31 to 0.66 and were significant in all but one case. However, none of the alternative metrics were strong predictors of the source control performance of cloth masks. Our results suggest that a better understanding of the relationships between source control performance and metrics like filtration efficiency, airflow resistance, and fit factor are needed to develop simple methods to estimate the effectiveness of masks as source control devices for respiratory aerosols. |
Multi-instrument assessment of fine and ultrafine titanium dioxide aerosols
Ranpara A , LeBouf RF , Nurkiewicz TR , Yi J , Cumpston JL , Stefaniak AB . J Toxicol Environ Health A 2022 86 (1) 1-22 The measurement of fine (diameter: 100 nanometers-2.5 micrometers) and ultrafine (UF: < 100 nanometers) titanium dioxide (TiO(2)) particles is instrument dependent. Differences in measurements exist between toxicological and field investigations for the same exposure metric such as mass, number, or surface area because of variations in instruments used, operating parameters, or particle-size measurement ranges. Without appropriate comparison, instrument measurements create a disconnect between toxicological and field investigations for a given exposure metric. Our objective was to compare a variety of instruments including multiple metrics including mass, number, and surface area (SA) concentrations for assessing different concentrations of separately aerosolized fine and UF TiO(2) particles. The instruments studied were (1) DustTrak™ DRX, (2) personal DataRAMs™ (PDR), (3) GRIMM(TM), and (4) diffusion charger (DC). Two devices of each field-study instrument (DRX, PDR, GRIMM, and DC) were used to measure various metrics while adjusting for gravimetric mass concentrations of fine and UF TiO(2) particles in controlled chamber tests. An analysis of variance (ANOVA) was used to apportion the variance to inter-instrument (between different instrument-types), inter-device (within instrument), and intra-device components. Performance of each instrument-device was calculated using root mean squared error compared to reference methods: close-faced cassette and gravimetric analysis for mass and scanning mobility particle sizer (SMPS) real-time monitoring for number and SA concentrations. Generally, inter-instrument variability accounted for the greatest (62.6% or more) source of variance for mass, and SA-based concentrations of fine and UF TiO(2) particles. However, higher intra-device variability (53.7%) was observed for number concentrations measurements with fine particles compared to inter-instrument variability (40.8%). Inter-device variance range(0.5-5.5%) was similar for all exposure metrics. DRX performed better in measuring mass closer to gravimetric than PDRs for fine and UF TiO(2). Number concentrations measured by GRIMMs and SA measurements by DCs were considerably (40.8-86.9%) different from the reference (SMPS) method for comparable size ranges of fine and UF TiO(2). This information may serve to aid in interpreting assessments in risk models, epidemiologic studies, and development of occupational exposure limits, relating to health effect endpoints identified in toxicological studies considering similar instruments evaluated in this study. |
Aerosol physicochemical determinants of carbon black and ozone inhalation co-exposure induced pulmonary toxicity
Majumder N , Kodali V , Velayutham M , Goldsmith T , Amedro J , Khramtsov VV , Erdely A , Nurkiewicz TR , Harkema JR , Kelley EE , Hussain S . Toxicol Sci 2022 191 (1) 61-78 Air pollution accounts for more than 7 million premature deaths worldwide. Using ultrafine carbon black (CB) and ozone (O3) as a model for an environmental co-exposure scenario, the dose response relationships in acute pulmonary injury and inflammation were determined by generating, characterizing, and comparing stable concentrations of CB aerosols (2.5, 5.0, 10.0mg/m3), O3 (0.5, 1.0, 2.0ppm) with mixture CB+O3 (2.5+0.5, 5.0+1.0, 10.0+2.0). C57BL6 male mice were exposed for 3hours by whole body inhalation and acute toxicity determined after 24h. CB itself did not cause any alteration, however, a dose response in pulmonary injury/inflammation was observed with O3 and CB+O3. This increase in response with mixtures was not dependent on the uptake but due to enhanced reactivity of the particles. Benchmark dose modeling showed several-fold increase in potency with CB+O3 compared to CB or O3 alone. Principal component analysis provided insight into response relationships between various doses and treatments. There was a significant correlation in lung responses with charge-based size distribution, total/alveolar deposition, oxidant generation and antioxidant depletion potential. Lung tissue gene/protein response demonstrated distinct patterns that are better predicted by either particle dose/aerosol responses (IL-1, KC, TGF-) or particle reactivity (TSLP, IL13, IL-6). Hierarchical clustering showed a distinct signature with high dose and a similarity in mRNA expression pattern of low and medium doses of CB+O3. In conclusion, we demonstrate that the biological outcomes from CB+O3 co-exposure are significantly greater than individual exposures over a range of aerosol concentrations and aerosol characteristics can predict biological outcome. |
Face mask fit modifications that improve source control performance.
Blachere FM , Lemons AR , Coyle JP , Derk RC , Lindsley WG , Beezhold DH , Woodfork K , Duling MG , Boutin B , Boots T , Harris JR , Nurkiewicz T , Noti JD . Am J Infect Control 2021 50 (2) 133-140 BACKGROUND: During the COVID-19 pandemic, face masks are used as source control devices to reduce the expulsion of respiratory aerosols from infected people. Modifications such as mask braces, earloop straps, knotting and tucking, and double masking have been proposed to improve mask fit however the data on source control are limited. METHODS: The effectiveness of mask fit modifications was determined by conducting fit tests on human subjects and simulator manikins and by performing simulated coughs and exhalations using a source control measurement system. RESULTS: Medical masks without modification blocked ≥56% of cough aerosols and ≥42% of exhaled aerosols. Modifying fit by crossing the earloops or placing a bracket under the mask did not increase performance, while using earloop toggles, an earloop strap, and knotting and tucking the mask increased performance. The most effective modifications for improving source control performance were double masking and using a mask brace. Placing a cloth mask over a medical mask blocked ≥85% of cough aerosols and ≥91% of exhaled aerosols. Placing a brace over a medical mask blocked ≥95% of cough aerosols and ≥99% of exhaled aerosols. CONCLUSIONS: Fit modifications can greatly improve the performance of face masks as source control devices for respiratory aerosols. |
Oxidized carbon black nanoparticles induce endothelial damage through C-X-C chemokine receptor 3-mediated pathway
Majumder N , Velayutham M , Bitounis D , Kodali VK , Hasan Mazumder MH , Amedro J , Khramtsov VV , Erdely A , Nurkiewicz T , Demokritou P , Kelley EE , Hussain S . Redox Biol 2021 47 102161 Oxidation of engineered nanomaterials during application in various industrial sectors can alter their toxicity. Oxidized nanomaterials also have widespread industrial and biomedical applications. In this study, we evaluated the cardiopulmonary hazard posed by these nanomaterials using oxidized carbon black (CB) nanoparticles (CB(ox)) as a model particle. Particle surface chemistry was characterized by X-ray photo electron spectroscopy (XPS) and Fourier-transform infrared spectroscopy (FTIR). Colloidal characterization and in vitro dosimetry modeling (particle kinetics, fate and transport modeling) were performed. Lung inflammation was assessed following oropharyngeal aspiration of CB or oxidized CB(ox) particles (20 μg per mouse) in C57BL/6J mice. Toxicity and functional assays were also performed on murine macrophage (RAW 264.7) and endothelial cell lines (C166) with and without pharmacological inhibitors. Oxidant generation was assessed by electron paramagnetic resonance spectroscopy (EPR) and via flow cytometry. Endothelial toxicity was evaluated by quantifying pro-inflammatory mRNA expression, monolayer permeability, and wound closure. XPS and FTIR spectra indicated surface modifications, the appearance of new functionalities, and greater oxidative potential (both acellular and in vitro) of CB(ox) particles. Treatment with CB(ox) demonstrated greater in vivo inflammatory potentials (lavage neutrophil counts, secreted cytokine, and lung tissue mRNA expression) and air-blood barrier disruption (lavage proteins). Oxidant-dependent pro-inflammatory signaling in macrophages led to the production of CXCR3 ligands (CXCL9,10,11). Conditioned medium from CB(ox)-treated macrophages induced significant elevation in endothelial cell pro-inflammatory mRNA expression, enhanced monolayer permeability and impairment of scratch healing in CXCR3 dependent manner. In summary, this study mechanistically demonstrated an increased biological potency of CB(ox) particles and established the role of macrophage-released chemical mediators in endothelial damage. |
Oxidant-induced epithelial alarmin pathway mediates lung inflammation and functional decline following ultrafine carbon and ozone inhalation co-exposure
Majumder N , Goldsmith WT , Kodali VK , Velayutham M , Friend SA , Khramtsov VV , Nurkiewicz TR , Erdely A , Zeidler-Erdely PC , Castranova V , Harkema JR , Kelley EE , Hussain S . Redox Biol 2021 46 102092 Environmental inhalation exposures are inherently mixed (gases and particles), yet regulations are still based on single toxicant exposures. While the impacts of individual components of environmental pollution have received substantial attention, the impact of inhalation co-exposures is poorly understood. Here, we mechanistically investigated pulmonary inflammation and lung function decline after inhalation co-exposure and individual exposures to ozone (O(3)) and ultrafine carbon black (CB). Environmentally/occupationally relevant lung deposition levels in mice were achieved after inhalation of stable aerosols with similar aerodynamic and mass median distributions. X-ray photoemission spectroscopy detected increased surface oxygen contents on particles in co-exposure aerosols. Compared with individual exposures, co-exposure aerosols produced greater acellular and cellular oxidants detected by electron paramagnetic resonance (EPR) spectroscopy, and in vivo immune-spin trapping (IST), as well as synergistically increased lavage neutrophils, lavage proteins and inflammation related gene/protein expression. Co-exposure induced a significantly greater respiratory function decline compared to individual exposure. A synthetic catalase-superoxide dismutase mimetic (EUK-134) significantly blunted lung inflammation and respiratory function decline confirming the role of oxidant imbalance. We identified a significant induction of epithelial alarmin (thymic stromal lymphopoietin-TSLP)-dependent interleukin-13 pathway after co-exposure, associated with increased mucin and interferon gene expression. We provided evidence of interactive outcomes after air pollution constituent co-exposure and identified a key mechanistic pathway that can potentially explain epidemiological observation of lung function decline after an acute peak of air pollution. Developing and studying the co-exposure scenario in a standardized and controlled fashion will enable a better mechanistic understanding of how environmental exposures result in adverse outcomes. |
A comparison of performance metrics for cloth masks as source control devices for simulated cough and exhalation aerosols.
Lindsley WG , Blachere FM , Beezhold DH , Law BF , Derk RC , Hettick JM , Woodfork K , Goldsmith WT , Harris JR , Duling MG , Boutin B , Nurkiewicz T , Boots T , Coyle J , Noti JD . Aerosol Sci Technol 2021 55 (10) 1125-1142 Universal mask wearing is recommended to help control the spread of COVID-19. Masks reduce the expulsion of aerosols of respiratory fluids into the environment (called source control) and offer some protection to the wearer. Masks are often characterized using filtration efficiency, airflow resistance, and manikin or human fit factors, which are standard metrics used for personal protective devices. However, none of these metrics are direct measurements of how effectively a mask blocks coughed and exhaled aerosols. We studied the source control performance of 15 cloth masks (face masks, neck gaiters, and bandanas), two medical masks, and two N95 filtering facepiece respirators by measuring their ability to block aerosols ≤7 µm expelled during simulated coughing and exhalation (called source control collection efficiency). These measurements were compared with filtration efficiencies, airflow resistances, and fit factors measured on manikin headforms and humans. Collection efficiencies for the cloth masks ranged from 17% to 71% for coughing and 35% to 66% for exhalation. Filtration efficiencies for the cloth masks ranged from 1.4% to 98%, while the fit factors were 1.3 to 7.4 on headforms and 1.0 to 4.0 on human subjects. The Spearman’s rank correlation coefficients between the source control collection efficiencies and the standard metrics ranged from 0.03 to 0.68 and were significant in all but two cases. However, none of the standard metrics were strongly correlated with source control performance. A better understanding of the relationships between source control collection efficiency, filtration efficiency, airflow resistance, and fit factor is needed. ©, This work was authored as part of the Contributor's official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 USC. 105, no copyright protection is available for such works under US Law. |
Inhalation of welding fumes reduced sperm counts and high fat diet reduced testosterone levels; differential effects in Sprague Dawley and Brown Norway rats
Skovmand A , Erdely A , Antonini JM , Nurkiewicz TR , Shoeb M , Eye T , Kodali V , Loeschner K , Vidmar J , Agerholm JS , Goericke-Pesch S , Vogel U , Hougaard KS . Part Fibre Toxicol 2020 17 (1) 2 BACKGROUND: Previous studies have shown that inhalation of welding fumes may induce pulmonary and systemic inflammation and organ accumulation of metal, to which spermatogenesis and endocrine function may be sensitive. Also obesity may induce low-grade systemic inflammation. This study aimed to investigate the effects on sperm production of inhaled metal nanoparticles from stainless steel welding, and the potential exacerbation by intake of a high fat diet. Both the inbred Brown Norway and the outbred Sprague Dawley rat strains were included to study the influence of strain on the detection of toxicity. Rats were fed regular or high fat (HF) diet for 24 weeks and were exposed to 20 mg/m(3) of gas metal arc-stainless steel (GMA-SS) welding fumes or filtered air for 3 h/day, 4 days/week for 5 weeks, during weeks 7-12. Outcomes were assessed upon termination of exposure (week 12) and after recovery (week 24). RESULTS: At week 12, the GMA-SS exposure induced pulmonary inflammation in both strains, without consistent changes in markers of systemic inflammation (CRP, MCP-1, IL-6 and TNFalpha). GMA-SS exposure lowered daily sperm production compared to air controls in Sprague Dawley rats, but only in GMA-SS Brown Norway rats also fed the HF diet. Overall, HF diet rats had lower serum testosterone levels compared to rats on regular diet. Metal content in the testes was assessed in a limited number of samples in Brown Norway rats, but no increase was obsedrved. At week 24, bronchoalveolar lavage cell counts had returned to background levels for GMA-SS exposed Sprague Dawley rats but remained elevated in Brown Norway rats. GMA-SS did not affect daily sperm production statistically significantly at this time point, but testicular weights were lowered in GMA-SS Sprague Dawley rats. Serum testosterone remained lowered in Sprague Dawley rats fed the HF diet. CONCLUSION: Exposure to GMA-SS welding fumes lowered sperm production in two strains of rats, whereas high fat diet lowered serum testosterone. The effect on sperm counts was likely not mediated by inflammation or lowered testosterone levels. The studied reproductive outcomes seemed more prone to disruption in the Sprague Dawley compared to the Brown Norway strain. |
Particle and organic vapor emissions from children's 3-D pen and 3-D printer toys
Yi J , Duling MG , Bowers LN , Knepp AK , LeBouf RF , Nurkiewicz TR , Ranpara A , Luxton T , Martin SB Jr , Burns DA , Peloquin DM , Baumann EJ , Virji MA , Stefaniak AB . Inhal Toxicol 2019 31 1-14 Objective: Fused filament fabrication "3-dimensional (3-D)" printing has expanded beyond the workplace to 3-D printers and pens for use by children as toys to create objects.Materials and methods: Emissions from two brands of toy 3-D pens and one brand of toy 3-D printer were characterized in a 0.6 m(3) chamber (particle number, size, elemental composition; concentrations of individual and total volatile organic compounds (TVOC)). The effects of print parameters on these emission metrics were evaluated using mixed-effects models. Emissions data were used to model particle lung deposition and TVOC exposure potential.Results: Geometric mean particle yields (10(6)-10(10) particles/g printed) and sizes (30-300 nm) and TVOC yields (<detectable to 590 microg TVOC/g printed) for the toys were similar to those from 3-D printers used in workplaces. Metal emissions included manganese (1.6-92.3 ng/g printed) and lead (0.13-1.2 ng/g printed). Among toys, extruder nozzle conditions (diameter, temperature) and filament (type, color, and extrusion speed) significantly influenced particle and TVOC emissions. Dose modeling indicated that emitted particles would deposit in the lung alveoli of children. Exposure modeling indicated that TVOC concentration from use of a single toy would be 1-31 microg/m(3) in a classroom and 3-154 microg/m(3) in a residential living room.Discussion: Potential exists for inhalation of organic vapors and metal-containing particles during use of these toys.Conclusions: If deemed appropriate, e.g. where multiple toys are used in a poorly ventilated area or a toy is positioned near a child's breathing zone, control technologies should be implemented to reduce emissions and exposure risk. |
Maternal engineered nanomaterial inhalation during gestation disrupts vascular kisspeptin reactivity
Bowdridge EC , Abukabda AB , Engles KJ , McBride CR , Batchelor TP , Goldsmith WT , Garner KL , Friend S , Nurkiewicz TR . Toxicol Sci 2019 169 (2) 524-533 Maternal engineered nanomaterial (ENM) inhalation is associated with uterine vascular impairments and endocrine disruption that may lead to altered gestational outcomes. We have shown that nano-titanium dioxide (nano-TiO2) inhalation impairs endothelium-dependent uterine arteriolar dilation in pregnant rats. However, the mechanism underlying this dysfunction is unknown. Due to its role as a potent vasoconstrictor and essential reproductive hormone, we examined how kisspeptin is involved in nano-TiO2-induced vascular dysfunction and placental efficiency. Pregnant Sprague-Dawley rats were exposed (gestational day (GD) 10) to nano-TiO2 aerosols (cumulative dose=525+/-16 mug; n = 8) or sham-exposed (n = 6) and sacrificed on GD 20. Plasma was collected to evaluate estrogen (E2), progesterone (P4), prolactin (PRL), corticosterone (CORT), and kisspeptin. Pup and placental weights were measured to calculate placental efficiency (grams fetus/gram placental). Additionally, pressure myography was used to determine uterine artery vascular reactivity. Contractile responses were assessed via cumulative additions of kisspeptin (1 x 10-9 to 1 x 10-4 M). Estrogen was decreased at GD 20 in exposed (11.08+/-3 pg/mL) vs. sham-control rats (66.97+/-3 pg/mL), whereas there were no differences in P4, PRL, CORT or kisspeptin. Placental weights were increased in exposed (0.99+/-0.03 g) vs. sham-control rats (0.70+/-0.04 g), whereas pup weights (4.01+/-0.47 g vs. 4.15+/-0.15 g) and placental efficiency (4.5+/-0.2 vs. 6.4+/-0.5) were decreased in exposed rats. Maternal ENM inhalation exposure augmented uterine artery vasoconstrictor responses to kisspeptin (91.2%+/-2.0 vs. 98.6%+/-0.10). These studies represent initial evidence that pulmonary maternal ENM exposure perturbs the normal gestational endocrine vascular axis via a kisspeptin-dependent mechanism, and decreased placental, which may adversely affect health outcomes. |
miRNA-378a as a key regulator of cardiovascular health following engineered nanomaterial inhalation exposure.
Hathaway QA , Durr AJ , Shepherd DL , Pinti MV , Brandebura AN , Nichols CE , Kunovac A , Goldsmith WT , Friend SA , Abukabda AB , Fink GK , Nurkiewicz TR , Hollander JM . Nanotoxicology 2019 13 (5) 1-20 Nano-titanium dioxide (nano-TiO2), though one of the most utilized and produced engineered nanomaterials (ENMs), diminishes cardiovascular function through dysregulation of metabolism and mitochondrial bioenergetics following inhalation exposure. The molecular mechanisms governing this cardiac dysfunction remain largely unknown. The purpose of this study was to elucidate molecular mediators that connect nano-TiO2 exposure with impaired cardiac function. Specifically, we were interested in the role of microRNA (miRNA) expression in the resulting dysfunction. Not only are miRNA global regulators of gene expression, but also miRNA-based therapeutics provide a realistic treatment modality. Wild type and MiRNA-378a knockout mice were exposed to nano-TiO2 with an aerodynamic diameter of 182 +/- 1.70 nm and a mass concentration of 11.09 mg/m(3) for 4 h. Cardiac function, utilizing the Vevo 2100 Imaging System, electron transport chain complex activities, and mitochondrial respiration assessed cardiac and mitochondrial function. Immunoblotting and qPCR examined molecular targets of miRNA-378a. MiRNA-378a-3p expression was increased 48 h post inhalation exposure to nano-TiO2. Knockout of miRNA-378a preserved cardiac function following exposure as revealed by preserved E/A ratio and E/SR ratio. In knockout animals, complex I, III, and IV activities ( approximately 2- to 6-fold) and fatty acid respiration ( approximately 5-fold) were significantly increased. MiRNA-378a regulated proteins involved in mitochondrial fusion, transcription, and fatty acid metabolism. MiRNA-378a-3p acts as a negative regulator of mitochondrial metabolic and biogenesis pathways. MiRNA-378a knockout animals provide a protective effect against nano-TiO2 inhalation exposure by altering mitochondrial structure and function. This is the first study to manipulate a miRNA to attenuate the effects of ENM exposure. |
Maternal titanium dioxide nanomaterial inhalation exposure compromises placental hemodynamics
Abukabda AB , Bowdridge EC , McBride CR , Batchelor TP , Goldsmith WT , Garner KL , Friend S , Nurkiewicz TR . Toxicol Appl Pharmacol 2019 367 51-61 The fetal consequences of gestational engineered nanomaterial (ENM) exposure are unclear. The placenta is a barrier protecting the fetus and allowing transfer of substances from the maternal circulation. The purpose of this study was to determine the effects of maternal pulmonary titanium dioxide nanoparticle (nano-TiO2) exposure on the placenta and umbilical vascular reactivity. We hypothesized that pulmonary nano-TiO2 inhalation exposure increases placental vascular resistance and impairs umbilical vascular responsiveness. Pregnant Sprague-Dawley rats were exposed via whole-body inhalation to nano-TiO2 with an aerodynamic diameter of 188+/-0.36nm. On gestational day (GD) 11, rats began inhalation exposures (6h/exposure). Daily lung deposition was 87.5+/-2.7mug. Animals were exposed for 6days for a cumulative lung burden of 525+/-16mug. On GD 20, placentas, umbilical artery and vein were isolated, cannulated, and treated with acetylcholine (ACh), angiotensin II (ANGII), S-nitroso-N-acetyl-DL-penicillamine (SNAP), or calcium-free superfusate (Ca(2+)-free). Mean outflow pressure was measured in placental units. ACh increased outflow pressure to 53+/-5mmHg in sham-controls but only to 35+/-4mmHg in exposed subjects. ANGII decreased outflow pressure in placentas from exposed animals (17+/-7mmHg) compared to sham-controls (31+/-6mmHg). Ca(2+)-free superfusate yielded maximal outflow pressures in sham-control (63+/-5mmHg) and exposed (30+/-10mmHg) rats. Umbilical artery endothelium-dependent dilation was decreased in nano-TiO2 exposed fetuses (30+/-9%) compared to sham-controls (58+/-6%), but ANGII sensitivity was increased (-79+/-20% vs -36+/-10%). These results indicate that maternal gestational pulmonary nano-TiO2 exposure increases placental vascular resistance and impairs umbilical vascular reactivity. |
Group II innate lymphoid cells and microvascular dysfunction from pulmonary titanium dioxide nanoparticle exposure
Abukabda AB , McBride CR , Batchelor TP , Goldsmith WT , Bowdridge EC , Garner KL , Friend S , Nurkiewicz TR . Part Fibre Toxicol 2018 15 (1) 43 BACKGROUND: The cardiovascular effects of pulmonary exposure to engineered nanomaterials (ENM) are poorly understood, and the reproductive consequences are even less understood. Inflammation remains the most frequently explored mechanism of ENM toxicity. However, the key mediators and steps between lung exposure and uterine health remain to be fully defined. The purpose of this study was to determine the uterine inflammatory and vascular effects of pulmonary exposure to titanium dioxide nanoparticles (nano-TiO2). We hypothesized that pulmonary nano-TiO2 exposure initiates a Th2 inflammatory response mediated by Group II innate lymphoid cells (ILC2), which may be associated with an impairment in uterine microvascular reactivity. METHODS: Female, virgin, Sprague-Dawley rats (8-12 weeks) were exposed to 100 mug of nano-TiO2 via intratracheal instillation 24 h prior to microvascular assessments. Serial blood samples were obtained at 0, 1, 2 and 4 h post-exposure for multiplex cytokine analysis. ILC2 numbers in the lungs were determined. ILC2s were isolated and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) levels were measured. Pressure myography was used to assess vascular reactivity of isolated radial arterioles. RESULTS: Pulmonary nano-TiO2 exposure was associated with an increase in IL-1ss, 4, 5 and 13 and TNF- alpha 4 h post-exposure, indicative of an innate Th2 inflammatory response. ILC2 numbers were significantly increased in lungs from exposed animals (1.66 +/- 0.19%) compared to controls (0.19 +/- 0.22%). Phosphorylation of the transactivation domain (Ser-468) of NF-kappaB in isolated ILC2 and IL-33 in lung epithelial cells were significantly increased (126.8 +/- 4.3% and 137 +/- 11% of controls respectively) by nano-TiO2 exposure. Lastly, radial endothelium-dependent arteriolar reactivity was significantly impaired (27 +/- 12%), while endothelium-independent dilation (7 +/- 14%) and alpha-adrenergic sensitivity (8 +/- 2%) were not altered compared to control levels. Treatment with an anti- IL-33 antibody (1 mg/kg) 30 min prior to nano-TiO2 exposure resulted in a significant improvement in endothelium-dependent dilation and a decreased level of IL-33 in both plasma and bronchoalveolar lavage fluid. CONCLUSIONS: These results provide evidence that the uterine microvascular dysfunction that follows pulmonary ENM exposure may be initiated via activation of lung-resident ILC2 and subsequent systemic Th2-dependent inflammation. |
Microvascular dysfunction following multi-walled carbon nanotube exposure is mediated by thrombospondin-1 receptor CD47
Mandler WK , Nurkiewicz TR , Porter DW , Kelley EE , Olfert IM . Toxicol Sci 2018 165 (1) 90-99 Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) disrupts peripheral microvascular function. Thrombospondin-1 (TSP-1) is highly expressed during lung injury and has been shown to alter microvascular reactivity. It is unclear exactly how TSP-1 exerts effects on vascular function, but we hypothesized that the TSP-1 receptor CD47 may mediate changes in vasodilation.Wildtype (WT) or CD47 knockout (CD47 KO) C57B6/J-background animals were exposed to 50 microg of MWCNT or saline control via pharyngeal aspiration. Twenty-four hours post-exposure, intravital microscopy was performed to assess arteriolar dilation and venular leukocyte adhesion and rolling. To assess tissue redox status, electron paramagnetic resonance and NOx measurements were performed, while inflammatory biomarkers were measured via multiplex assay.Vasodilation was impaired in the WT+MWCNT group compared to control (57+/-9% vs 90+/-2% relaxation), while CD47 KO animals showed no impairment (108+/-8% relaxation). Venular leukocyte adhesion and rolling increased by > 2-fold, while the CD47 KO group showed no change. Application of the antioxidant apocynin rescued normal leukocyte activity in the WT+MWCNT group. Lung and plasma NOx were reduced in the WT+MWCNT group by 47% and 32%, respectively, while the CD47 KO groups were unchanged from control. Some inflammatory cytokines were increased in the CD47+MWCNT group only.In conclusion, TSP-1 is an important ligand mediating MWCNT-induced microvascular dysfunction, and CD47 is a component of this dysregulation. CD47 activation likely disrupts nitric oxide (*NO) signaling and promotes leukocyte-endothelial interactions. Impaired *NO production, signaling, and bioavailability is linked to a variety of cardiovascular diseases in which TSP-1/CD47 may play an important role. |
Inhalation exposure to three-dimensional printer emissions stimulates acute hypertension and microvascular dysfunction
Stefaniak AB , LeBouf RF , Duling MG , Yi J , Abukabda AB , McBride CR , Nurkiewicz TR . Toxicol Appl Pharmacol 2017 335 1-5 Fused deposition modeling (FDM), or three-dimensional (3D) printing has become routine in industrial, occupational and domestic environments. We have recently reported that 3D printing emissions (3DPE) are complex mixtures, with a large ultrafine particulate matter component. We and others have reported that inhalation of xenobiotic particles in this size range is associated with an array of cardiovascular dysfunctions. Sprague-Dawley rats were exposed to 3DPE aerosols via nose-only exposure for ~3h. Twenty-four hours later, intravital microscopy was performed to assess microvascular function in the spinotrapezius muscle. Endothelium-dependent and -independent arteriolar dilation were stimulated by local microiontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). At the time of experiments, animals exposed to 3DPE inhalation presented with a mean arterial pressure of 125+/-4mmHg, and this was significantly higher than that for the sham-control group (94+/-3mmHg). Consistent with this pressor response in the 3DPE group, was an elevation of ~12% in resting arteriolar tone. Endothelium-dependent arteriolar dilation was significantly impaired after 3DPE inhalation across all iontophoretic ejection currents (0-27+/-15%, compared to sham-control: 15-120+/-21%). Endothelium-independent dilation was not affected by 3DPE inhalation. These alterations in peripheral microvascular resistance and reactivity are consistent with elevations in arterial pressure that follow 3DPE inhalation. Future studies must identify the specific toxicants generated by FDM that drive this acute pressor response. |
Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation
Mandler WK , Nurkiewicz TR , Porter DW , Olfert IM . Nanotoxicology 2016 11 (1) 1-31 Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) has been shown to disrupt endothelium-dependent arteriolar dilation in the peripheral microcirculation. The molecular mechanisms behind these arteriolar disruptions have yet to be fully elucidated. The secreted matricellular matrix protein thrombospondin-1 (TSP-1) is capable of moderating arteriolar vasodilation by inhibiting soluble guanylate cyclase activity. We hypothesized that TSP-1 may be a link between nanomaterial exposure and observed peripheral microvascular dysfunction. To test this hypothesis, wild-type C57B6J (WT) and TSP-1 knockout (KO) mice were exposed via lung aspiration to 50 microg MWCNT or a sham dispersion medium control. Following exposure (24hrs), arteriolar characteristics and reactivity were measured in the gluteus maximus muscle using intravital microscopy (IVM) coupled with microiontophoretic delivery of acetylcholine (ACh) or sodium nitroprusside (SNP). In WT mice exposed to MWCNT, skeletal muscle TSP-1 protein increased > 5-fold compared to sham exposed, and exhibited a 39% and 47% decrease in endothelium-dependent and independent vasodilation, respectively. In contrast, TSP-1 protein was not increased following MWCNT exposure in KO mice and exhibited no loss in dilatory capacity. Microvascular leukocyte leukocyte-endothelium interactions were measured by leukocyte adhesion and rolling activity in assessing third order venules. The WT+MWCNT group demonstrated 223% higher leukocyte rolling compared to WT+SHAM controls. TSP-1 KO animals exposed to MWCNT showed no differences from WT+SHAM control. These data provide evidence that TSP-1 is likely a central mediator of the systemic microvascular dysfunction that follows pulmonary MWCNT exposure. |
Emission of particulate matter from a desktop three-dimensional (3D) printer
Yi J , LeBouf RF , Duling MG , Nurkiewicz T , Chen BT , Schwegler-Berry D , Virji MA , Stefaniak AB . J Toxicol Environ Health A 2016 79 (11) 1-13 Desktop three-dimensional (3D) printers are becoming commonplace in business offices, public libraries, university labs and classrooms, and even private homes; however, these settings are generally not designed for exposure control. Prior experience with a variety of office equipment devices such as laser printers that emit ultrafine particles (UFP) suggests the need to characterize 3D printer emissions to enable reliable risk assessment. The aim of this study was to examine factors that influence particulate emissions from 3D printers and characterize their physical properties to inform risk assessment. Emissions were evaluated in a 0.5-m3 chamber and in a small room (32.7 m3) using real-time instrumentation to measure particle number, size distribution, mass, and surface area. Factors evaluated included filament composition and color, as well as the manufacturer-provided printer emissions control technologies while printing an object. Filament type significantly influenced emissions, with acrylonitrile butadiene styrene (ABS) emitting larger particles than polylactic acid (PLA), which may have been the result of agglomeration. Geometric mean particle sizes and total particle (TP) number and mass emissions differed significantly among colors of a given filament type. Use of a cover on the printer reduced TP emissions by a factor of 2. Lung deposition calculations indicated a threefold higher PLA particle deposition in alveoli compared to ABS. Desktop 3D printers emit high levels of UFP, which are released into indoor environments where adequate ventilation may not be present to control emissions. Emissions in nonindustrial settings need to be reduced through the use of a hierarchy of controls, beginning with device design, followed by engineering controls (ventilation) and administrative controls such as choice of filament composition and color. |
Cardiac and mitochondrial dysfunction following acute pulmonary exposure to mountaintop removal mining particulate matter
Nichols CE , Shepherd DL , Knuckles TL , Thapa D , Stricker JC , Stapleton PA , Minarchick VC , Erdely A , Zeidler-Erdely PC , Alway SE , Nurkiewicz TR , Hollander JM . Am J Physiol Heart Circ Physiol 2015 309 (12) ajpheart 00353 2015 Throughout the United States, air pollution correlates with adverse health outcomes and cardiovascular disease incidence is commonly increased following environmental exposure. In areas surrounding active mountaintop removal mines (MTM) a further increase in cardiovascular morbidity is observed and may be attributed in part to particulate matter (PM) released from the mine. The mitochondrion has been shown to be central in the etiology of many cardiovascular diseases, yet its role in PM related cardiovascular effects are not realized. In this study we sought to elucidate the cardiac processes that are disrupted following exposure to mountaintop removal mining particulate matter (PMMTM). To address this question we exposed male Sprague-Dawley rats to PMMTM, collected within one mile of an active MTM site, using intratracheal instillation. Twenty-four hours following exposure we evaluated cardiac function, apoptotic indices and mitochondrial function. PMMTM exposure, elicited a significant decrease in ejection fraction and fractional shortening compared to controls. Investigation into the cellular impacts of PMMTM exposure identified a significant increase in mitochondrial-induced apoptosis as reflected by an increase in TUNEL positive nuclei and increased caspase-3 and -9 activities. Finally, a significant increase in mitochondrial transition pore opening leading to decreased mitochondrial function was identified following exposure. In conclusion, our data suggest that pulmonary exposure to PMMTM increases cardiac mitochondrial-associated apoptosis and decreases mitochondrial function concomitant with decreased cardiac function. These results suggest that increased cardiovascular disease incidence in populations surrounding MTM mines may be associated with increased cardiac cell apoptosis and decreased mitochondrial function. |
Acute inflammatory responses of nanoparticles in an intra-tracheal instillation rat model
Armstead AL , Minarchick VC , Porter DW , Nurkiewicz TR , Li B . PLoS One 2015 10 (3) e0118778 Exposure to hard metal tungsten carbide cobalt (WC-Co) "dusts" in enclosed industrial environments is known to contribute to the development of hard metal lung disease and an increased risk for lung cancer. Currently, the influence of local and systemic inflammation on disease progression following WC-Co exposure remains unclear. To better understand the relationship between WC-Co nanoparticle (NP) exposure and its resultant effects, the acute local pulmonary and systemic inflammatory responses caused by WC-Co NPs were explored using an intra-tracheal instillation (IT) model and compared to those of CeO2 (another occupational hazard) NP exposure. Sprague-Dawley rats were given an IT dose (0-500 mug per rat) of WC-Co or CeO2 NPs. Following 24-hr exposure, broncho-alveolar lavage fluid and whole blood were collected and analyzed. A consistent lack of acute local pulmonary inflammation was observed in terms of the broncho-alveolar lavage fluid parameters examined (i.e. LDH, albumin, and macrophage activation) in animals exposed to WC-Co NP; however, significant acute pulmonary inflammation was observed in the CeO2 NP group. The lack of acute inflammation following WC-Co NP exposure contrasts with earlier in vivo reports regarding WC-Co toxicity in rats, illuminating the critical role of NP dose and exposure time and bringing into question the potential role of impurities in particle samples. Further, we demonstrated that WC-Co NP exposure does not induce acute systemic effects since no significant increase in circulating inflammatory cytokines were observed. Taken together, the results of this in vivo study illustrate the distinct differences in acute local pulmonary and systemic inflammatory responses to NPs composed of WC-Co and CeO2; therefore, it is important that the outcomes of pulmonary exposure to one type of NPs may not be implicitly extrapolated to other types of NPs. |
Intravenous and gastric cerium dioxide nanoparticle exposure disrupts microvascular smooth muscle signaling
Minarchick VC , Stapleton PA , Fix NR , Leonard SS , Sabolsky EM , Nurkiewicz TR . Toxicol Sci 2014 144 (1) 77-89 Cerium dioxide nanoparticles (CeO2 NP) hold great therapeutic potential, but the in vivo effects of non-pulmonary exposure routes are unclear. The first aim was to determine whether microvascular function is impaired after intravenous and gastric CeO2 NP exposure. The second aim was to investigate the mechanism(s) of action underlying microvascular dysfunction following CeO2 NP exposure. Rats were exposed to CeO2 NP (primary diameter: 4 +/- 1 nm, surface area: 81.36 m2/g) by intratracheal instillation, intravenous injection, or gastric gavage. Mesenteric arterioles were harvested 24 h post-exposure and vascular function was assessed using an isolated arteriole preparation. Endothelium-dependent and -independent function and vascular smooth muscle (VSM) signaling [soluble guanylyl cyclase (sGC), and cyclic guanosine monophosphate (cGMP)] were assessed. Reactive oxygen species (ROS) generation and nitric oxide (NO) production were analyzed. Compared to controls, endothelium-dependent and -independent dilation were impaired following intravenous injection (by 61% and 45%) and gastric gavage (by 63% and 49%). However, intravenous injection resulted in greater microvascular impairment (16% and 35%) compared to gastric gavage at an identical dose (100 mug). Furthermore, sGC activation and cGMP responsiveness were impaired following pulmonary, intravenous, and gastric CeO2 NP treatment. Finally, nanoparticle exposure resulted in route-dependent, increased ROS generation and decreased NO production. These results indicate that CeO2 NP exposure route differentially impairs microvascular function, which may be mechanistically linked to decreased NO production and subsequent VSM signaling. Fully understanding the mechanisms behind CeO2 NP in vivo effects is a critical step in the continued therapeutic development of this nanoparticle. |
Pulmonary cerium dioxide nanoparticle exposure differentially impairs coronary and mesenteric arteriolar reactivity
Minarchick VC , Stapleton PA , Porter DW , Wolfarth MG , Ciftyurek E , Barger M , Sabolsky EM , Nurkiewicz TR . Cardiovasc Toxicol 2013 13 (4) 323-37 Cerium dioxide nanoparticles (CeO2 NPs) are an engineered nanomaterial (ENM) that possesses unique catalytic, oxidative, and reductive properties. Currently, CeO2 NPs are being used as a fuel catalyst but these properties are also utilized in the development of potential drug treatments for radiation and stroke protection. These uses of CeO2 NPs present a risk for human exposure; however, to date, no studies have investigated the effects of CeO2 NPs on the microcirculation following pulmonary exposure. Previous studies in our laboratory with other nanomaterials have shown impairments in normal microvascular function after pulmonary exposures. Therefore, we predicted that CeO2 NP exposure would cause microvascular dysfunction that is dependent on the tissue bed and dose. Twenty-four-hour post-exposure to CeO2 NPs (0-400 mug), mesenteric, and coronary arterioles was isolated and microvascular function was assessed. Our results provided evidence that pulmonary CeO2 NP exposure impairs endothelium-dependent and endothelium-independent arteriolar dilation in a dose-dependent manner. The CeO2 NP exposure dose which causes a 50 % impairment in arteriolar function (EC50) was calculated and ranged from 15 to 100 mug depending on the chemical agonist and microvascular bed. Microvascular assessments with acetylcholine revealed a 33-75 % reduction in function following exposure. Additionally, there was a greater sensitivity to CeO2 NP exposure in the mesenteric microvasculature due to the 40 % decrease in the calculated EC50 compared to the coronary microvasculature EC50. CeO2 NP exposure increased mean arterial pressure in some groups. Taken together, these observed microvascular changes may likely have detrimental effects on local blood flow regulation and contribute to cardiovascular dysfunction associated with particle exposure. |
Nanotechnology: toxicologic pathology
Hubbs AF , Sargent LM , Porter DW , Sager TM , Chen BT , Frazer DG , Castranova V , Sriram K , Nurkiewicz TR , Reynolds SH , Battelli LA , Schwegler-Berry D , McKinney W , Fluharty KL , Mercer RR . Toxicol Pathol 2013 41 (2) 395-409 Nanotechnology involves technology, science, and engineering in dimensions less than 100 nm. A virtually infinite number of potential nanoscale products can be produced from many different molecules and their combinations. The exponentially increasing number of nanoscale products will solve critical needs in engineering, science, and medicine. However, the virtually infinite number of potential nanotechnology products is a challenge for toxicologic pathologists. Because of their size, nanoparticulates can have therapeutic and toxic effects distinct from micron-sized particulates of the same composition. In the nanoscale, distinct intercellular and intracellular translocation pathways may provide a different distribution than that obtained by micron-sized particulates. Nanoparticulates interact with subcellular structures including microtubules, actin filaments, centrosomes, and chromatin; interactions that may be facilitated in the nanoscale. Features that distinguish nanoparticulates from fine particulates include increased surface area per unit mass and quantum effects. In addition, some nanotechnology products, including the fullerenes, have a novel and reactive surface. Augmented microscopic procedures including enhanced dark-field imaging, immunofluorescence, field-emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy are useful when evaluating nanoparticulate toxicologic pathology. Thus, the pathology assessment is facilitated by understanding the unique features at the nanoscale and the tools that can assist in evaluating nanotoxicology studies. |
Impairment of coronary arteriolar endothelium-dependent dilation after multi-walled carbon nanotube inhalation: a time-course study
Stapleton P , Minarchick V , Cumpston A , McKinney W , Chen B , Sager T , Frazer D , Mercer R , Scabilloni J , Andrew M , Castranova V , Nurkiewicz T . Int J Mol Sci 2012 13 (11) 13781-13803 Engineered nanomaterials have been developed for widespread applications due to many highly unique and desirable characteristics. The purpose of this study was to assess pulmonary inflammation and subepicardial arteriolar reactivity in response to multi-walled carbon nanotube (MWCNT) inhalation and evaluate the time course of vascular alterations. Rats were exposed to MWCNT aerosols producing pulmonary deposition. Pulmonary inflammation via bronchoalveolar lavage and MWCNT translocation from the lungs to systemic organs was evident 24 h post-inhalation. Coronary arterioles were evaluated 24-168 h post-exposure to determine microvascular response to changes in transmural pressure, endothelium-dependent and -independent reactivity. Myogenic responsiveness, vascular smooth muscle reactivity to nitric oxide, and a-adrenergic responses all remained intact. However, a severe impact on endothelium-dependent dilation was observed within 24 h after MWCNT inhalation, a condition which improved, but did not fully return to control after 168 h. In conclusion, results indicate that MWCNT inhalation not only leads to pulmonary inflammation and cytotoxicity at low lung burdens, but also a low level of particle translocation to systemic organs. MWCNT inhalation also leads to impairments of endothelium-dependent dilation in the coronary microcirculation within 24 h, a condition which does not fully dissipate within 168 h. The innovations within the field of nanotechnology, while exciting and novel, can only reach their full potential if toxicity is first properly assessed. |
Nanoparticle inhalation alters systemic arteriolar vasoreactivity through sympathetic and cyclooxygenase-mediated pathways
Knuckles TL , Yi J , Frazer DG , Leonard HD , Chen BT , Castranova V , Nurkiewicz TR . Nanotoxicology 2011 6 (7) 724-35 The widespread increase in the production and use of nanomaterials has increased the potential for nanoparticle exposure; however, the biological effects of nanoparticle inhalation are poorly understood. Rats were exposed to nanosized titanium dioxide aerosols (10 mcg lung burden); at 24 h post-exposure, the spinotrapezius muscle was prepared for intravital microscopy. Nanoparticle exposure did not alter perivascular nerve stimulation (PVNS)-induced arteriolar constriction under normal conditions; however, adrenergic receptor inhibition revealed a more robust effect. Nanoparticle inhalation reduced arteriolar dilation in response to active hyperaemia (AH). In both PVNS and AH experiments, nitric oxide synthase (NOS) inhibition affected only controls. Whereas cyclooxygenase (COX) inhibition only attenuated AH-induced arteriolar dilation in nanoparticle-exposed animals. This group displayed an enhanced U46619 constriction and attenuated iloprost-induced dilation. Collectively, these studies indicate that nanoparticle exposure reduces microvascular NO bioavailability and alters COX-mediated vasoreactivity. Furthermore, the enhanced adrenergic receptor sensitivity suggests an augmented sympathetic responsiveness. |
Nanotoxicology--a pathologist's perspective
Hubbs AF , Mercer RR , Benkovic SA , Harkema J , Sriram K , Schwegler-Berry D , Goravanahally MP , Nurkiewicz TR , Castranova V , Sargent LM . Toxicol Pathol 2011 39 (2) 301-24 Advances in chemistry and engineering have created a new technology, nanotechnology, involving the tiniest known manufactured products. These products have a rapidly increasing market share and appear poised to revolutionize engineering, cosmetics, and medicine. Unfortunately, nanotoxicology, the study of nanoparticulate health effects, lags behind advances in nanotechnology. Over the past decade, existing literature on ultrafine particles and respirable durable fibers has been supplemented by studies of first-generation nanotechnology products. These studies suggest that nanosizing increases the toxicity of many particulates. First, as size decreases, surface area increases, thereby speeding up dissolution of soluble particulates and exposing more of the reactive surface of durable but reactive particulates. Second, nanosizing facilitates movement of particulates across cellular and intracellular barriers. Third, nanosizing allows particulates to interact with, and sometimes even hybridize with, subcellular structures, including in some cases microtubules and DNA. Finally, nanosizing of some particulates, increases pathologic and physiologic responses, including inflammation, fibrosis, allergic responses, genotoxicity, and carcinogenicity, and may alter cardiovascular and lymphatic function. Knowing how the size and physiochemical properties of nanoparticulates affect bioactivity is important in assuring that the exciting new products of nanotechnology are used safely. This review provides an introduction to the pathology and toxicology of nanoparticulates. |
Nanoparticle inhalation impairs coronary microvascular reactivity via a local reactive oxygen species-dependent mechanism
LeBlanc AJ , Moseley AM , Chen BT , Frazer D , Castranova V , Nurkiewicz TR . Cardiovasc Toxicol 2010 10 (1) 27-36 We have shown that nanoparticle inhalation impairs endothelium-dependent vasodilation in coronary arterioles. It is unknown whether local reactive oxygen species (ROS) contribute to this effect. Rats were exposed to TiO(2) nanoparticles via inhalation to produce a pulmonary deposition of 10 microg. Coronary arterioles were isolated from the left anterior descending artery distribution, and responses to acetylcholine, arachidonic acid, and U46619 were assessed. Contributions of nitric oxide synthase and prostaglandin were assessed via competitive inhibition with N(G)-Monomethyl-L-Arginine (L-NMMA) and indomethacin. Microvascular wall ROS were quantified via dihydroethidium (DHE) fluorescence. Coronary arterioles from rats exposed to nano-TiO(2) exhibited an attenuated vasodilator response to ACh, and this coincided with a 45% increase in DHE fluorescence. Coincubation with 2,2,6,6-tetramethylpiperidine-N-oxyl and catalase ameliorated impairments in ACh-induced vasodilation from nanoparticle exposed rats. Incubation with either L-NMMA or indomethacin significantly attenuated ACh-induced vasodilation in sham-control rats, but had no effect in rats exposed to nano-TiO(2). Arachidonic acid induced vasoconstriction in coronary arterioles from rats exposed to nano-TiO(2), but dilated arterioles from sham-control rats. These results suggest that nanoparticle exposure significantly impairs endothelium-dependent vasoreactivity in coronary arterioles, and this may be due in large part to increases in microvascular ROS. Furthermore, altered prostanoid formation may also contribute to this dysfunction. Such disturbances in coronary microvascular function may contribute to the cardiac events associated with exposure to particles in this size range. |
Nanoparticle inhalation impairs endothelium-dependent vasodilation in subepicardial arterioles
LeBlanc AJ , Cumpston JL , Chen BT , Frazer D , Castranova V , Nurkiewicz TR . J Toxicol Environ Health A 2009 72 (24) 1576-1584 Exposure to fine particulate matter (PM, mean aerodynamic diameter <= 2.5 mu m) has been shown to be a risk factor for cardiovascular disease mortality and may contribute to acute coronary events such as myocardial infarction (MI). There is sufficient reason to believe that smaller particles, such as nanoparticles, might be even more detrimental than larger sized particles due to their increased surface area and higher pulmonary deposition. Our laboratory showed that nanoparticle inhalation impairs endothelium-dependent arteriolar vasodilation in skeletal muscle. However, it is not known whether coronary microvascular endothelial function is affected in a similar manner. Rats were exposed to filtered air (control) or TiO2 nanoparticles (primary particle diameter, similar to 21 nm) via inhalation at concentrations that produced measured depositions (10 mu g) relevant to ambient air pollution. Subepicardial arterioles(similar to 150 mm in diameter) were isolated and responses to transmural pressure, flow-induced dilation (FID), acetylcholine (ACh), the Ca2+ ionophore A23187, and sodium nitroprusside (SNP) were assessed. Myogenic responsiveness was preserved between groups. In addition, there was no difference in the vasodilation to SNP, signifying that smooth muscle sensitivity to nitric oxide (NO) is unaffected by nano-TiO2 exposure. However, inhalation of nano-TiO2 produced an increase in spontaneous tone in coronary arterioles and also impaired endothelium-dependent FID. In addition, ACh-induced and A23187-induced vasodilation was also blunted in arterioles after inhalation of nano-TiO2. Data showed that nanoparticle exposure significantly impairs endothelium-dependent vasodilation in subepicardial arterioles. Such disturbances in coronary microvascular function are consistent with the cardiac events associated with particle pollution exposure. |
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