Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-30 (of 98 Records) |
Query Trace: Kashon ML[original query] |
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High-fat Western diet alters crystalline silica-induced airway epithelium ion transport but not airway smooth muscle reactivity
Thompson JA , Kashon ML , McKinney W , Fedan JS . BMC Res Notes 2024 17 (1) 13 OBJECTIVES: Silicosis is an irreversible occupational lung disease resulting from crystalline silica inhalation. Previously, we discovered that Western diet (HFWD)-consumption increases susceptibility to silica-induced pulmonary inflammation and fibrosis. This study investigated the potential of HFWD to alter silica-induced effects on airway epithelial ion transport and smooth muscle reactivity. METHODS: Six-week-old male F344 rats were fed a HFWD or standard rat chow (STD) and exposed to silica (Min-U-Sil 5(®), 15 mg/m(3), 6 h/day, 5 days/week, for 39 d) or filtered air. Experimental endpoints were measured at 0, 4, and 8 weeks post-exposure. Transepithelial potential difference (V(t)), short-circuit current (I(SC)) and transepithelial resistance (R(t)) were measured in tracheal segments and ion transport inhibitors [amiloride, Na(+) channel blocker; NPPB; Cl- channel blocker; ouabain, Na(+), K(+)-pump blocker] identified changes in ion transport pathways. Changes in airway smooth muscle reactivity to methacholine (MCh) were investigated in the isolated perfused trachea preparation. RESULTS: Silica reduced basal I(SC) at 4 weeks and HFWD reduced the I(SC) response to amiloride at 0 week compared to air control. HFWD + silica exposure induced changes in ion transport 0 and 4 weeks after treatment compared to silica or HFWD treatments alone. No effects on airway smooth muscle reactivity to MCh were observed. |
Biological effects of inhaled crude oil vapor. III. Pulmonary inflammation, cytotoxicity, and gene expression profile
Sager TM , Joseph P , Umbright CM , Hubbs AF , Barger M , Kashon ML , Fedan JS , Roberts JR . Inhal Toxicol 2023 35 1-13 ![]() OBJECTIVE: Workers may be exposed to vapors emitted from crude oil in upstream operations in the oil and gas industry. Although the toxicity of crude oil constituents has been studied, there are very few in vivo investigations designed to mimic crude oil vapor (COV) exposures that occur in these operations. The goal of the current investigation was to examine lung injury, inflammation, oxidant generation, and effects on the lung global gene expression profile following a whole-body acute or sub-chronic inhalation exposure to COV. MATERIALS AND METHODS: To conduct this investigation, rats were subjected to either a whole-body acute (6 hr) or a sub-chronic (28 d) inhalation exposure (6 hr/d × 4 d/wk × 4 wk) to COV (300 ppm; Macondo well surrogate oil). Control rats were exposed to filtered air. One and 28 d after acute exposure, and 1, 28, and 90 d following sub-chronic exposure, bronchoalveolar lavage was performed on the left lung to collect cells and fluid for analyses, the apical right lobe was preserved for histopathology, and the right cardiac and diaphragmatic lobes were processed for gene expression analyses. RESULTS: No exposure-related changes were identified in histopathology, cytotoxicity, or lavage cell profiles. Changes in lavage fluid cytokines indicative of inflammation, immune function, and endothelial function after sub-chronic exposure were limited and varied over time. Minimal gene expression changes were detected only at the 28 d post-exposure time interval in both the exposure groups. CONCLUSION: Taken together, the results from this exposure paradigm, including concentration, duration, and exposure chamber parameters, did not indicate significant and toxicologically relevant changes in markers of injury, oxidant generation, inflammation, and gene expression profile in the lung. |
Interleukin-11 receptor subunit alpha-1 is required for maximal airway responsiveness to methacholine following acute exposure to ozone.
Johnston RA , Atkins CL , Siddiqui SR , Jackson WT , Mitchell NC , Spencer CY , Pilkington AWth , Kashon ML , Haque IU . Am J Physiol Regul Integr Comp Physiol 2022 323 (6) R921-R934 ![]() Interleukin (IL)-11, a multi-functional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit alpha-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of non-atopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 would attenuate lung inflammation and increases in airway responsiveness following acute inhalation exposure to ozone (O(3)), a criteria pollutant and non-atopic asthma stimulus. Accordingly, four- and/or twenty-four hours following cessation of exposure to filtered room air or O(3), we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O(3)-exposed IL-11Rα1-deficient as compared to O(3)-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O(3)-exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared to wild-type mice following O(3) exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of non-atopic asthma. |
High-fat western diet consumption exacerbates silica-induced pulmonary inflammation and fibrosis
Thompson JA , Johnston RA , Price RE , Hubbs AF , Kashon ML , McKinney W , Fedan JS . Toxicol Rep 2022 9 1045-1053 Consumption of a high-fat Western diet (HFWD) contributes to obesity, disrupted adipose endocrine function, and development of metabolic dysfunction (MetDys). Impaired lung function, pulmonary hypertension, and asthma are all associated with MetDys. Over 35% of adults in the U.S. have MetDys, yet interactions between MetDys and hazardous occupational inhalation exposures are largely unknown. Occupational silica-inhalation leads to chronic lung inflammation, progressive fibrosis, and significant respiratory morbidity and mortality. In this study, we aim to determine the potential of HFWD-consumption to alter silica-induced inflammatory responses in the lung. Six-wk old male F344 rats fed a high fat Western diet (HFWD; 45 kcal % fat, sucrose 22.2% by weight) to induce MetDys, or standard rat chow (STD, controls) for 16 wk were subsequently exposed to silica (6 h/d, 5 d/wk, 39 d; Min-U-Sil 5®, 15 mg/m(3)) or filtered air; animals remained on their assigned diet for the study duration. Indices of lung inflammation and histopathologic assessment of lung tissue were quantified at 0, 4, and 8 wk after cessation of exposure. Combined HFWD+silica exposure increased bronchoalveolar lavage (BAL) total cells, leukocytes, and BAL lactate dehydrogenase compared to STD+silica exposure controls at all timepoints. HFWD+silica exposure increased BAL proinflammatory cytokines at 4 and 8 wk compared to STD+silica exposure. At 8 wk, histopathological analysis confirmed that alveolitis, epithelial cell hypertrophy and hyperplasia, lipoproteinosis, fibrosis, bronchoalveolar lymphoid hyperplasia and granulomas were exacerbated in the HFWD+silica-exposed group compared to STD+silica-exposed controls. Our results suggest an increased susceptibility to silica-induced lung disease caused by HFWD consumption. |
Biological effects of inhaled crude oil vapor. II. Pulmonary effects
Fedan JS , Thompson JA , Russ KA , Dey RD , Reynolds JS , Kashon ML , Jackson MC , McKinney W . Toxicol Appl Pharmacol 2022 450 116154 Workers involved in oil exploration and production in the upstream petroleum industry are exposed to crude oil vapor (COV). COV levels in the proximity of workers during production tank gauging and opening of thief hatches can exceed regulatory standards, and several deaths have occurred after opening thief hatches. There is a paucity of information regarding the effects of COV inhalation in the lung. To address these knowledge gaps, the present hazard identification study was undertaken to investigate the effects of an acute, single inhalation exposure (6h) or a 28 d sub-chronic exposure (6h/d4 d/wk 4 wks) to COV (300ppm; Macondo well surrogate oil) on ventilatory and non-ventilatory functions of the lung in a rat model 1 and 28 d after acute exposure, and 1, 28 and 90 d following sub-chronic exposure. Basal airway resistance was increased 90 d post-sub-chronic exposure, but reactivity to methacholine (MCh) was unaffected. In the isolated, perfused trachea preparation the inhibitory effect of the airway epithelium on reactivity to MCh was increased at 90 d post-exposure. Efferent cholinergic nerve activity regulating airway smooth muscle was unaffected by COV exposure. Acute exposure did not affect basal airway epithelial ion transport, but 28 d after sub-chronic exposure alterations in active (Na(+) and Cl) and passive ion transport occurred. COV treatment did not affect lung vascular permeability. The findings indicate that acute and sub-chronic COV inhalation does not appreciably affect ventilatory properties of the rat, but transient changes in airway epithelium occur. |
Biological effects of inhaled crude oil vapor V. Altered biogenic amine neurotransmitters and neural protein expression
Sriram K , Lin GX , Jefferson AM , McKinney W , Jackson MC , Cumpston JL , Cumpston JB , Leonard HD , Kashon ML , Fedan JS . Toxicol Appl Pharmacol 2022 449 116137 Workers in the oil and gas industry are at risk for exposure to a number of physical and chemical hazards at the workplace. Chemical hazard risks include inhalation of crude oil or its volatile components. While several studies have investigated the neurotoxic effects of volatile hydrocarbons, in general, there is a paucity of studies assessing the neurotoxicity of crude oil vapor (COV). Consequent to the 2010 Deepwater Horizon (DWH) oil spill, there is growing concern about the short- and long-term health effects of exposure to COV. NIOSH surveys suggested that the DWH oil spill cleanup workers experienced neurological symptoms, including depression and mood disorders, but the health effects apart from oil dispersants were difficult to discern. To investigate the potential neurological risks of COV, male Sprague-Dawley rats were exposed by whole-body inhalation to COV (300ppm; Macondo surrogate crude oil) following an acute (6h/d1 d) or sub-chronic (6h/d4 d/wk.4 wks) exposure regimen. At 1, 28 or 90 d post-exposure, norepinephrine (NE), epinephrine (EPI), dopamine (DA) and serotonin (5-HT) were evaluated as neurotransmitter imbalances are associated with psychosocial-, motor- and cognitive- disorders. Sub-chronic COV exposure caused significant reductions in NE, EPI and DA in the dopaminergic brain regions, striatum (STR) and midbrain (MB), and a large increase in 5-HT in the STR. Further, sub-chronic exposure to COV caused upregulation of synaptic and Parkinson's disease-related proteins in the STR and MB. Whether such effects will lead to neurodegenerative outcomes remain to be investigated. |
Pulmonary toxicity and gene expression changes in response to whole-body inhalation exposure to multi-walled carbon nanotubes in rats
Sager TM , Umbright CM , Mustafa GM , Roberts JR , Orandle MS , Cumpston JL , McKinney WG , Boots T , Kashon ML , Joseph P . Inhal Toxicol 2022 34 1-19 Purpose: To investigate the molecular mechanisms underlying the pulmonary toxicity induced by exposure to one form of multi-walled carbon nanotubes (MWCNT-7).Materials and methods: Rats were exposed, by whole-body inhalation, to air or an aerosol containing MWCNT-7 particles at target cumulative doses (concentration x time) ranging from 22.5 to 180 (mg/m(3))h over a three-day (6 hours/day) period and toxicity and global gene expression profiles were determined in the lungs.Results: MWCNT-7 particles, associated with alveolar macrophages (AMs), were detected in rat lungs following the exposure. Mild to moderate lung pathological changes consisting of increased cellularity, thickening of the alveolar wall, alveolitis, fibrosis, and granuloma formation were detected. Bronchoalveolar lavage (BAL) toxicity parameters such as lactate dehydrogenase activity, number of AMs and polymorphonuclear leukocytes (PMNs), intracellular oxidant generation by phagocytes, and levels of cytokines were significantly (p < 0.05) increased in response to exposure to MWCNT-7. Global gene expression profiling identified several significantly differentially expressed genes (fold change >1.5 and FDR p value <0.05) in all the MWCNT-7 exposed rats. Bioinformatic analysis of the gene expression data identified significant enrichment of several diseases/biological function categories (for example, cancer, leukocyte migration, inflammatory response, mitosis, and movement of phagocytes) and canonical pathways (for example, kinetochore metaphase signaling pathway, granulocyte and agranulocyte adhesion and diapedesis, acute phase response, and LXR/RXR activation). The alterations in the lung toxicity parameters and gene expression changes exhibited a dose-response to the MWCNT exposure.Conclusions: Taken together, the data provided insights into the molecular mechanisms underlying the pulmonary toxicity induced by inhalation exposure of rats to MWCNT-7. |
Biological effects of crude oil vapor. IV. Cardiovascular effects
Krajnak K , Russ KA , McKinney W , Waugh S , Zheng W , Kan H , Kashon ML , Cumpston J , Fedan JS . Toxicol Appl Pharmacol 2022 447 116071 Workers in the oil and gas extraction industry are at risk of inhaling volatile organic compounds. Epidemiological studies suggest oil vapor inhalation may affect cardiovascular health. Thus, in this hazard identification study we investigated the effects of inhalation of crude oil vapor (COV) on cardiovascular function. Male rats were exposed to air or COV (300ppm) for 6h (acute), or 6h/day 4 d/wk. 4 wk. (sub-chronic). The effects of COV inhalation were assessed 1, 28, and 90 d post-exposure. Acute exposure to COV resulted in a reduction in mean arterial and diastolic blood pressures 1 and 28 d after exposure, changes in nitrate-nitrite and H(2)O(2) levels, and in the expression of transcripts and proteins that regulate inflammation, vascular remodeling, and the synthesis of NO in the heart and kidneys. The sub-chronic exposure resulted in a reduced sensitivity to (1)-adrenoreceptor-mediated vasoconstriction in vitro 28 d post-exposure, and a reduction in oxidative stress in the heart. Sub-chronic COV exposure led to alterations in the expression of NO synthases and anti-oxidant enzymes, which regulate inflammation and oxidative stress in the heart and kidneys. There seems to be a balance between changes in the expression of transcripts associated with the generation of reactive oxygen species (ROS) and antioxidant enzymes. The ability of antioxidant enzymes to reduce or inhibit the effects of ROS may allow the cardiovascular system to adapt to acute COV exposures. However, sub-chronic exposures may result in longer-lasting negative health consequences on the cardiovascular system. |
Interactions of a high-fat Western diet and crystalline silica inhalation on airway epithelial ion transport and airway reactivity
Thompson JA , Kashon ML , McKinney WS , Fedan JS . FASEB J 2022 36 Silicosis, an irreversible occupational lung disease caused by crystalline silica inhalation, is a serious health risk for silica-exposed workers. NIOSH reports that Appalachian coal miners have higher rates of obesity and metabolic dysfunction (MetDys) compared to the general U.S. adult population. MetDys is a risk factor for lung function impairment, pulmonary hypertension, and asthma. Consumption of a high-fat Western diet (HFWD) is associated with obesity and MetDys. In this study, we investigated the effects of, and determine interactions between, HFWD-consumption and silica-exposure on airway epithelial ion transport and smooth muscle reactivity in the F344 rat. Six-week-old male F344 rats were fed either a HFWD [40.6% fat (19.5% lard), 40.6% total carbohydrate (20% sucrose), 14.8 % protein] or standard rat chow (STD) [6.2 % fat, 44.2 % carbohydrate (grain sources), 18.6 % protein] for the duration of the study. Following 16 weeks of diet-consumption, inhalation exposure to respirable crystalline silica (Min-U-Sil 5® , 15 mg/m3 , 6 h/d, 5 d/wk, for 39 d) or filtered air began, with endpoint experiments conducted at 0, 4, and 8 wk post-exposure. Airway epithelial ion transport maintains airway surface liquid osmolarity and depth required for effective cilia motility and clearance of xenogens. Changes in ion transport were determined ex vivo by measurement of transepithelial potential difference (Vt ), short-circuit current (ISC ) and transepithelial resistance (Rt ) in rat tracheal segments mounted in Ussing chambers, and administered the ion transport inhibitors amiloride (Na+ channel blocker; apical), 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB; Cl- channel blocker; apical), and ouabain (Na+ , K+ -pump blocker; basolateral). Airway hyperresponsiveness is associated with obesity and pulmonary diseases such as asthma and COPD; thus, the isolated perfused trachea apparatus was employed to ascertain whether silica or HFWD altered airway smooth muscle reactivity to serosal or mucosal applied methacholine (MCh). HFWD-consumption had no effect on basal Vt . Silica exposure increased Na+ transport at 0 wk, decreased basal ISC at 4 wk, and reduced Cl- channel and Na+ , K+ -pump activity at both 4 wk and 8 wk compared to STD+AIR controls. HFWD-consumption caused a reduction in Cl- transport and Na+ , K+ -pump activity at 4 wk, while increasing Rt in response to ouabain at 0 wk and NPPB at 8 wk compared to STD+AIR. HFWD+SIL increased basal ISC at 0 and 4 wk, caused reduction in Cl- transport and Na+ , K+ -pump activity at 4 wk, while reducing Rt in response to ouabain at 4 wk compared to STD+SIL. No significant changes in tracheal reactivity to MCh were observed. In conclusion, HFWD and silica altered epithelial ion transport, but the combined effects of HFWD+SIL were not synergistic. © FASEB. |
Histopathology of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities in a murine model
Fraser K , Hubbs A , Yanamala N , Mercer RR , Stueckle TA , Jensen J , Eye T , Battelli L , Clingerman S , Fluharty K , Dodd T , Casuccio G , Bunker K , Lersch TL , Kashon ML , Orandle M , Dahm M , Schubauer-Berigan MK , Kodali V , Erdely A . Part Fibre Toxicol 2021 18 (1) 47 BACKGROUND: Multi-walled carbon nanotubes and nanofibers (CNT/F) have been previously investigated for their potential toxicities; however, comparative studies of the broad material class are lacking, especially those with a larger diameter. Additionally, computational modeling correlating physicochemical characteristics and toxicity outcomes have been infrequently employed, and it is unclear if all CNT/F confer similar toxicity, including histopathology changes such as pulmonary fibrosis. Male C57BL/6 mice were exposed to 40 µg of one of nine CNT/F (MW #1-7 and CNF #1-2) commonly found in exposure assessment studies of U.S. facilities with diameters ranging from 6 to 150 nm. Human fibroblasts (0-20 µg/ml) were used to assess the predictive value of in vitro to in vivo modeling systems. RESULTS: All materials induced histopathology changes, although the types and magnitude of the changes varied. In general, the larger diameter MWs (MW #5-7, including Mitsui-7) and CNF #1 induced greater histopathology changes compared to MW #1 and #3 while MW #4 and CNF #2 were intermediate in effect. Differences in individual alveolar or bronchiolar outcomes and severity correlated with physical dimensions and how the materials agglomerated. Human fibroblast monocultures were found to be insufficient to fully replicate in vivo fibrosis outcomes suggesting in vitro predictive potential depends upon more advanced cell culture in vitro models. Pleural penetrations were observed more consistently in CNT/F with larger lengths and diameters. CONCLUSION: Physicochemical characteristics, notably nominal CNT/F dimension and agglomerate size, predicted histopathologic changes and enabled grouping of materials by their toxicity profiles. Particles of greater nominal tube length were generally associated with increased severity of histopathology outcomes. Larger particle lengths and agglomerates were associated with more severe bronchi/bronchiolar outcomes. Spherical agglomerated particles of smaller nominal tube dimension were linked to granulomatous inflammation while a mixture of smaller and larger dimensional CNT/F resulted in more severe alveolar injury. |
High-fat western diet-consumption alters crystalline silica-induced serum adipokines, inflammatory cytokines and arterial blood flow in the F344 rat
Thompson JA , Krajnak K , Johnston RA , Kashon ML , McKinney W , Fedan JS . Toxicol Rep 2022 9 12-21 Adipose tissue (AT) plays a central role in the maintenance of whole-body energy homeostasis through release of adipokines. High-fat Western diet (HFWD)-consumption contributes to obesity, disruption of adipocyte metabolism, chronic systemic inflammation, and metabolic dysfunction (MetDys). MetDys is associated with impaired lung function, pulmonary hypertension, and asthma. Thirty-five percent of adults in the U.S. have MetDys, yet the impact of MetDys on susceptibility to occupational hazards is unknown. The aim of this study was to determine the potential of HFWD-consumption to alter inhaled crystalline silica dust-induced metabolic responses. Six-wk old male F344 rats were fed a HFWD (45 kcal % fat, sucrose 22.2 % by weight) or standard rat chow (STD, controls), and exposed to silica-inhalation (6 h/d, 5 d/wk, 39 d; Min-U-Sil 5®, 15 mg/m3) or filtered air. Indices of MetDys and systemic inflammation were measured at 0, 4, and 8 wk following cessation of silica exposure. At 8 wk post-exposure, silica reduced serum leptin and adiponectin levels, and increased arterial pulse frequency. HFWD-consumption induced weight gain, altered adipokines, liver, kidney, and pancreatic function, and increased tail artery blood flow. At 8 wk in HFWD + SIL-treated animals, the levels of serum pro-inflammatory cytokines (IFN-γ, CXCL-1, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-10 and IL-13) were increased compared to STD + SIL but were less than HFWD + AIR-induced levels. In conclusion, consumption of a HFWD altered silica-induced metabolic responses and silica exposure disrupted AT endocrine function. These findings demonstrate previously unknown interactions between HFWD-consumption and occupational silica exposure. © 2021 The Authors |
Investigation of particle transfer to sampler covers during the transportation of samples
Erekaife G , Park HD , Kashon ML , Chisholm WP , Lee EG . J Occup Environ Hyg 2021 18 (7) 1-10 This study investigated the effects of particle transfer to the covers of aerosol samplers during transportation of wood dust and welding fume samples. Wood dust samples were collected in a sanding chamber using four sampler types: closed-face cassettes (CFC), CFC with Accu-CAP inserts, disposable inhalable samplers (DIS), and Institute of Occupational Medicine (IOM). Welding fumes were collected in a walk-in chamber using the same samplers, with Solu-Sert replacing Accu-CAP. The samples were divided into two groups, with one group transported by air and the other by land. They were returned in the same manner and analyzed gravimetrically for wood dust and chemically for welding fumes. For wood dust, IOM showed a significantly higher percentage of particles transferred to the covers compared with the other samplers regardless of the transportation mode (p < 0.0001; 64% by air and 15% by land), while other samplers showed less than or close to 10% (3.5-12%). When the percentages of particle transfer to the covers were compared between the air and land transportation, both IOM and CFC samples showed differences between modes of transportation, while others did not. For welding fumes, most samples (61% of samples for copper [Cu] and 76% of samples for manganese [Mn]) showed nondetectable amounts of the analyte on the covers. For all samplers, the particle transfer to the covers for both transportation modes ranged from 0.2-33% for Cu and less than 4.5% for Mn. Overall, this study confirms that particle transfer to sampler covers during transport highly depends upon the transportation mode and sampler type for wood dust, whereas particle transfer seems minimal for welding fumes. The findings of this study are based on two materials and limited sample sizes. Further investigation considering different industry types and tasks, particle size ranges, and materials might be necessary. Nevertheless, occupational professionals should account for this transfer when handling and analyzing samples in practice. |
Differential Expression of Serum Exosome microRNAs and Cytokines in Influenza A and B Patients Collected in the 2016 and 2017 Influenza Seasons.
Othumpangat S , Lindsley WG , Beezhold DH , Kashon ML , Burrell CN , Mubareka S , Noti JD . Pathogens 2021 10 (2) ![]() ![]() MicroRNAs (miRNAs) have remarkable stability and are key regulators of mRNA transcripts for several essential proteins required for the survival of cells and replication of the virus. Exosomes are thought to play an essential role in intercellular communications by transporting proteins and miRNAs, making them ideal in the search for biomarkers. Evidence suggests that miRNAs are involved in the regulation of influenza virus replication in many cell types. During the 2016 and 2017 influenza season, we collected blood samples from 54 patients infected with influenza and from 30 healthy volunteers to identify the potential role of circulating serum miRNAs and cytokines in influenza infection. Data comparing the exosomal miRNAs in patients with influenza B to healthy volunteers showed 76 miRNAs that were differentially expressed (p < 0.05). In contrast, 26 miRNAs were differentially expressed between patients with influenza A (p < 0.05) and the controls. Of these miRNAs, 11 were commonly expressed in both the influenza A and B patients. Interferon (IFN)-inducing protein 10 (IP-10), which is involved in IFN synthesis during influenza infection, showed the highest level of expression in both influenza A and B patients. Influenza A patients showed increased expression of IFNα, GM-CSF, interleukin (IL)-13, IL-17A, IL-1β, IL-6 and TNFα, while influenza B induced increased levels of EGF, G-CSF, IL-1α, MIP-1α, and TNF-β. In addition, hsa-miR-326, hsa-miR-15b-5p, hsa-miR-885, hsa-miR-122-5p, hsa-miR-133a-3p, and hsa-miR-150-5p showed high correlations to IL-6, IL-15, IL-17A, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) with both strains of influenza. Next-generation sequencing studies of H1N1-infected human lung small airway epithelial cells also showed similar pattern of expression of miR-375-5p, miR-143-3p, 199a-3p, and miR-199a-5p compared to influenza A patients. In summary, this study provides insights into the miRNA profiling in both influenza A and B virus in circulation and a novel approach to identify the early infections through a combination of cytokines and miRNA expression. |
Physicochemical characterization and genotoxicity of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities.
Fraser K , Kodali V , Yanamala N , Birch ME , Cena L , Casuccio G , Bunker K , Lersch TL , Evans DE , Stefaniak A , Hammer MA , Kashon ML , Boots T , Eye T , Hubczak J , Friend SA , Dahm M , Schubauer-Berigan MK , Siegrist K , Lowry D , Bauer AK , Sargent LM , Erdely A . Part Fibre Toxicol 2020 17 (1) 62 ![]() BACKGROUND: Carbon nanotubes and nanofibers (CNT/F) have known toxicity but simultaneous comparative studies of the broad material class, especially those with a larger diameter, with computational analyses linking toxicity to their fundamental material characteristics was lacking. It was unclear if all CNT/F confer similar toxicity, in particular, genotoxicity. Nine CNT/F (MW #1-7 and CNF #1-2), commonly found in exposure assessment studies of U.S. facilities, were evaluated with reported diameters ranging from 6 to 150 nm. All materials were extensively characterized to include distributions of physical dimensions and prevalence of bundled agglomerates. Human bronchial epithelial cells were exposed to the nine CNT/F (0-24 μg/ml) to determine cell viability, inflammation, cellular oxidative stress, micronuclei formation, and DNA double-strand breakage. Computational modeling was used to understand various permutations of physicochemical characteristics and toxicity outcomes. RESULTS: Analyses of the CNT/F physicochemical characteristics illustrate that using detailed distributions of physical dimensions provided a more consistent grouping of CNT/F compared to using particle dimension means alone. In fact, analysis of binning of nominal tube physical dimensions alone produced a similar grouping as all characterization parameters together. All materials induced epithelial cell toxicity and micronuclei formation within the dose range tested. Cellular oxidative stress, DNA double strand breaks, and micronuclei formation consistently clustered together and with larger physical CNT/F dimensions and agglomerate characteristics but were distinct from inflammatory protein changes. Larger nominal tube diameters, greater lengths, and bundled agglomerate characteristics were associated with greater severity of effect. The portion of tubes with greater nominal length and larger diameters within a sample was not the majority in number, meaning a smaller percentage of tubes with these characteristics was sufficient to increase toxicity. Many of the traditional physicochemical characteristics including surface area, density, impurities, and dustiness did not cluster with the toxicity outcomes. CONCLUSION: Distributions of physical dimensions provided more consistent grouping of CNT/F with respect to toxicity outcomes compared to means only. All CNT/F induced some level of genotoxicity in human epithelial cells. The severity of toxicity was dependent on the sample containing a proportion of tubes with greater nominal lengths and diameters. |
Biological effects of inhaled hydraulic fracturing sand dust. IX. Summary and significance
Anderson SE , Barger M , Batchelor TP , Bowers LN , Coyle J , Cumpston A , Cumpston JL , Cumpston JB , Dey RD , Dozier AK , Fedan JS , Friend S , Hubbs AF , Jackson M , Jefferson A , Joseph P , Kan H , Kashon ML , Knepp AK , Kodali V , Krajnak K , Leonard SS , Lin G , Long C , Lukomska E , Marrocco A , Marshall N , Mc Kinney W , Morris AM , Olgun NS , Park JH , Reynolds JS , Roberts JR , Russ KA , Sager TM , Shane H , Snawder JE , Sriram K , Thompson JA , Umbright CM , Waugh S , Zheng W . Toxicol Appl Pharmacol 2020 409 115330 An investigation into the potential toxicological effects of fracking sand dust (FSD), collected from unconventional gas drilling sites, has been undertaken, along with characterization of their chemical and biophysical properties. Using intratracheal instillation of nine FSDs in rats and a whole body 4-d inhalation model for one of the FSDs, i.e., FSD 8, and related in vivo and in vitro experiments, the effects of nine FSDs on the respiratory, cardiovascular and immune systems, brain and blood were reported in the preceding eight tandem papers. Here, a summary is given of the key observations made in the organ systems reported in the individual studies. The major finding that inhaled FSD 8 elicits responses in extra-pulmonary organ systems is unexpected, as is the observation that the pulmonary effects of inhaled FSD 8 are attenuated relative to forms of crystalline silica more frequently used in animal studies, i.e., MIN-U-SIL®. An attempt is made to understand the basis for the extra-pulmonary toxicity and comparatively attenuated pulmonary toxicity of FSD 8. |
Biological effects of inhaled hydraulic fracturing sand dust. II. Particle characterization and pulmonary effects 30 d following intratracheal instillation
Fedan JS , Hubbs AF , Barger M , Schwegler-Berry D , Friend SA , Leonard SS , Thompson JA , Jackson MC , Snawder JE , Dozier AK , Coyle J , Kashon ML , Park JH , McKinney W , Roberts JR . Toxicol Appl Pharmacol 2020 409 115282 Hydraulic fracturing ("fracking") is used in unconventional gas drilling to allow for the free flow of natural gas from rock. Sand in fracking fluid is pumped into the well bore under high pressure to enter and stabilize fissures in the rock. In the process of manipulating the sand on site, respirable dust (fracking sand dust, FSD) is generated. Inhalation of FSD is a potential hazard to workers inasmuch as respirable crystalline silica causes silicosis, and levels of FSD at drilling work sites have exceeded occupational exposure limits set by OSHA. In the absence of any information about its potential toxicity, a comprehensive rat animal model was designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems (Fedan, J.S., Toxicol Appl Pharmacol. 00, 000-000, 2020). The present report, part of the larger investigation, describes: 1) a comparison of the physico-chemical properties of nine FSDs, collected at drilling sites, and MIN-U-SIL® 5, a reference silica dust, and 2) a comparison of the pulmonary inflammatory responses to intratracheal instillation of the nine FSDs and MIN-U-SIL® 5. Our findings indicate that, in many respects, the physico-chemical characteristics, and the biological effects of the FSDs and MIN-U-SIL® 5 after intratracheal instillation, have distinct differences. |
Biological effects of inhaled hydraulic fracturing sand dust. III. Cytotoxicity and pro-inflammatory responses in cultured murine macrophage cells
Olgun NS , Morris AM , Stefaniak AB , Bowers LN , Knepp AK , Duling MG , Mercer RR , Kashon ML , Fedan JS , Leonard SS . Toxicol Appl Pharmacol 2020 408 115281 Cultured murine macrophages (RAW 264.7) were used to investigate the effects of fracking sand dust (FSD) for its pro-inflammatory activity, in order to gain insight into the potential toxicity to workers associated with inhalation of FSD during hydraulic fracturing. While the role of respirable crystalline silica in the development of silicosis is well documented, nothing is known about the toxicity of inhaled FSD. The FSD (FSD 8) used in these studies was from an unconventional gas well drilling site. FSD 8was prepared as a 10 mg/ml stock solution in sterile PBS, vortexed for 15 s, and allowed to sit at room temperature for 30 min before applying the suspension to RAW 264.7cells. Compared to PBS controls, cellular viability was significantly decreased after a 24 h exposure to FSD. Intracellular reactive oxygen species (ROS) production and the production of IL-6, TNFα, and endothelin-1 (ET-1) were up-regulated as a result of the exposure, whereas the hydroxyl radical ((.)OH) was only detected in an acellular system. Immunofluorescent staining of cells against TNFα revealed that FSD 8 caused cellular blebbing, and engulfment of FSD 8 by macrophages was observed with enhanced dark-field microscopy. The observed changes in cellular viability, cellular morphology, free radical generation and cytokine production all confirm that FSD 8 is cytotoxic to RAW 264.7 cells and warrants future studies into the specific pathways and mechanisms by which these toxicities occur. |
Biological effects of inhaled hydraulic fracturing sand dust. IV. Pulmonary effects
Russ KA , Thompson JA , Reynolds JS , Mercer RR , Porter DW , McKinney W , Dey RD , Barger M , Cumpston J , Batchelor TP , Kashon ML , Kodali V , Jackson MC , Sriram K , Fedan JS . Toxicol Appl Pharmacol 2020 409 115284 Hydraulic fracturing creates fissures in subterranean rock to increase the flow and retrieval of natural gas. Sand ("proppant") in fracking fluid injected into the well bore maintains fissure patency. Fracking sand dust (FSD) is generated during manipulation of sand to prepare the fracking fluid. Containing respirable crystalline silica, FSD could pose hazards similar to those found in work sites where silica inhalation induces lung disease such as silicosis. This study was performed to evaluate the possible toxic effects following inhalation of a FSD (FSD 8) in the lung and airways. Rats were exposed (6 h/d × 4 d) to 10 or 30 mg/m(3) of a FSD, i.e., FSD 8, collected at a gas well, and measurements were performed 1, 7, 27 and, in one series of experiments, 90 d post-exposure. The following ventilatory and non-ventilatory parameters were measured in vivo and/or in vitro: 1) lung mechanics (respiratory system resistance and elastance, tissue damping, tissue elastance, Newtonian resistance and hysteresivity); 2) airway reactivity to inhaled methacholine (MCh); airway epithelium integrity (isolated, pefused trachea); airway efferent motor nerve activity (electric field stimulation in vitro); airway smooth muscle contractility; ion transport in intact and cultured epithelium; airway effector and sensory nerves; tracheal particle deposition; and neurogenic inflammation/vascular permeability. FSD 8 was without large effect on most parameters, and was not pro-inflammatory, as judged histologically and in cultured epithelial cells, but increased reactivity to inhaled MCh at some post-exposure time points and affected Na(+) transport in airway epithelial cells. |
Biological effects of inhaled hydraulic fracturing sand dust. V. Pulmonary inflammatory, cytotoxic and oxidant effects.
Sager TM , Roberts JR , Umbright CM , Barger M , Kashon ML , Fedan JS , Joseph P . Toxicol Appl Pharmacol 2020 408 115280 ![]() The pulmonary inflammatory response to inhalation exposure to a fracking sand dust (FSD 8) was investigated in a rat model. Adult male Sprague-Dawley rats were exposed by whole-body inhalation to air or an aerosol of a FSD, i.e., FSD 8, at concentrations of 10 or 30 mg/m(3), 6 h/d for 4 d. The control and FSD 8-exposed rats were euthanized at post-exposure time intervals of 1, 7 or 27 d and pulmonary inflammatory, cytotoxic and oxidant responses were determined. Deposition of FSD 8 particles was detected in the lungs of all the FSD 8-exposed rats. Analysis of bronchoalveolar lavage parameters of toxicity, oxidant generation, and inflammation did not reveal any significant persistent pulmonary toxicity in the FSD 8-exposed rats. Similarly, the lung histology of the FSD 8-exposed rats showed only minimal changes in influx of macrophages following the exposure. Determination of global gene expression profiles detected statistically significant differential expressions of only six and five genes in the 10 mg/m(3), 1-d post-exposure, and the 30 mg/m(3), 7-d post-exposure FSD 8 groups, respectively. Taken together, data obtained from the present study demonstrated that FSD 8 inhalation exposure resulted in no statistically significant toxicity or gene expression changes in the lungs of the rats. In the absence of any information about its potential toxicity, a comprehensive rat animal model study (see Fedan, J.S., Toxicol Appl Pharmacol. 000, 000-000, 2020) has been designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems. |
Biological effects of inhaled hydraulic fracturing sand dust. VI. Cardiovascular effects
Krajnak K , Kan H , Russ KA , McKinney W , Waugh S , Zheng W , Kashon ML , Johnson C , Cumpston J , Fedan JS . Toxicol Appl Pharmacol 2020 406 115242 Hydraulic fracturing is used to access oil and natural gas reserves. This process involves the high-pressure injection of fluid to fracture shale. Fracking fluid contains approximately 95% water, chemicals and 4.5% fracking sand. Workers may be exposed to fracking sand dust (FSD) during the manipulation of the sand, and negative health consequences could occur if FSD is inhaled. In the absence of any information about its potential toxicity, a comprehensive rat animal model study (see Fedan, J.S., Toxicol Appl Pharmacol. 000, 000-000, 2020) was designed to investigate the bioactivities of several FSDs in comparison to MIN-U-SIL® 5, a respirable α-quartz reference dust used in previous animal models of silicosis, in several organ systems. The goal of this study was to assess the effects of inhalation of one FSD, i.e., FSD 8, on factors and tissues that affect cardiovascular function. Male rats were exposed to 10 or 30 mg/m(3) FSD (6 h/d for 4 d) by whole body inhalation, with measurements made 1, 7 or 27 d post-exposure. One day following exposure to 10 mg/m(3) FSD the sensitivity to phenylephrine-induced vasoconstriction in tail arteries in vitro was increased. FSD exposure at both doses resulted in decreases in heart rate (HR), HR variability, and blood pressure in vivo. FSD induced changes in hydrogen peroxide concentrations and transcript levels for pro-inflammatory factors in heart tissues. In kidney, expression of proteins indicative of injury and remodeling was reduced after FSD exposure. When analyzed using regression analysis, changes in proteins involved in repair and remodeling were correlated. Thus, it appears that inhalation of FSD does have some prolonged effects on cardiovascular, and, possibly, renal function. The findings also provide information regarding potential mechanisms that may lead to these changes, and biomarkers that could be examined to monitor physiological changes that could be indicative of impending cardiovascular dysfunction. |
Tobacco smoke exposure exacerbated crystalline silica-induced lung toxicity in rats
Sager TM , Umbright CM , Mustafa GM , Yanamala N , Leonard HD , McKinney WG , Kashon ML , Joseph P . Toxicol Sci 2020 178 (2) 375-390 Smoking may modify the lung response to silica exposure including cancer and silicosis. Nevertheless, the precise role of exposure to tobacco smoke (TS) on the lung response to crystalline silica (CS) exposure and the underlying mechanisms need further clarification. The objectives of the present study were to determine the role of TS on lung response to CS exposure and the underlying mechanism(s). Male Fischer 344 rats were exposed by inhalation to air, CS (15 mg/m3, 6 hrs/day, 5 days), TS (80 mg/m3, 3 hrs/day, twice weekly, 6 months), or CS (15 mg/m3, 6 hrs/day, 5 days) followed by TS (80 mg/m3, 3 hrs/day, twice weekly, 6 months). The rats were euthanized 6 months and 3 weeks following initiation of the first exposure and the lung response was assessed. Silica exposure resulted in significant lung toxicity as evidenced by lung histological changes, enhanced neutrophil infiltration, increased LDH levels, enhanced oxidant production, and increased cytokine levels. The TS exposure alone had only a minimal effect on these toxicity parameters. However, the combined exposure to TS and CS exacerbated the lung response, compared to TS or CS exposure alone. Global gene expression changes in the lungs correlated with the lung toxicity severity. Bioinformatic analysis of the gene expression data demonstrated significant enrichment in functions, pathways, and networks relevant to the response to CS exposure which correlated with the lung toxicity detected. Collectively our data demonstrated an exacerbation of CS-induced lung toxicity by TS exposure and the molecular mechanisms underlying the exacerbated toxicity. |
Tumorigenic response in lung tumor susceptible A/J mice after sub-chronic exposure to calcium chromate or iron (III) oxide
Zeidler-Erdely PC , Falcone LM , Antonini JM , Fraser K , Kashon ML , Battelli LA , Salmen R , Trainor T , Grose L , Friend S , Yang C , Erdely A . Toxicol Lett 2020 334 60-65 Iron oxides are Group 3 (not classifiable as to its carcinogenicity to humans) according to the International Agency for Research on Cancer (IARC). Occupational exposures during iron and steel founding and hematite underground mining as well as other iron predominant exposures such as welding are Group 1 (carcinogenic to humans). The objective of this study was to investigate the potential of iron as iron (III) oxide (Fe(2)O(3)) to initiate lung tumors in A/J mice, a lung tumor susceptible strain. Male A/J mice were exposed by oropharyngeal aspiration to suspensions of Fe(2)O(3) (1 mg) or calcium chromate (CaCrO(4); 100 µg; positive control) for 26 weeks (once per week). Shams were exposed to 50 µL phosphate buffered saline (PBS; vehicle). Mice were euthanized 70 weeks after the first exposure and lung nodules were enumerated. Both CaCrO(4) and Fe(2)O(3) significantly increased gross-observed lung tumor multiplicity in A/J mice (9.63 ± 0.55 and 3.35 ± 0.30, respectively) compared to sham (2.31 ± 0.19). Histopathological analysis showed that bronchiolo-alveolar adenomas (BAA) and carcinomas (BAC) were the primary lung tumor types in all groups and were increased in the exposed groups compared to sham. BAC were significantly increased (146 %) in the CaCrO(4) group and neared significance in the Fe(2)O(3) group (100 % increase; p = 0.085). BAA and other histopathological indices of toxicity followed the same pattern with exposed groups increased compared to sham control. In conclusion, evidence from this study, in combination with our previous studies, demonstrate that exposure to iron alone may be a potential risk factor for lung carcinogenesis. |
Application of end-of-shift respirable crystalline silica monitoring to construction
Chien CH , Huang G , Lopez B , Morea A , Sing SY , Wu CY , Kashon ML , Harper M . J Occup Environ Hyg 2020 17 (9) 1-10 A pilot project was conducted to determine the effect of common construction dusts as interferences in a new portable end-of-shift (EoS), direct-on-filter (DoF) sampling and analysis method for respirable crystalline silica (RCS), in this case, quartz. Construction dusts were prepared from plaster, drywall, cement and brick by grinding, aerosolizing, and collecting respirable dust with high flow rate cyclones. Filters were loaded with different levels of commercial α-quartz powder Min-u-Sil 5, and different levels of interfering dusts, singly and in combination. Samples were analyzed by Fourier Transform Infrared Spectroscopy (FTIR). Good correlations were found between nominal quartz loading (0 µg, 25 µg, 50 µg, and 100 µg) adjusted for quartz in the interfering dust and FTIR absorbance alone and in the presence of all interfering dusts. The slopes of the correlations were similar whether the loading was quartz without interference, or with plaster, drywall, and cement dusts, regardless of quantity. The results show that (a) plaster and drywall dusts do not interfere substantially; (b) cement does not interfere, but a change in the intercept suggests an effect on the background absorbance of the filter; and (c) in addition to having a substantial quartz content, brick dust contains an additional material, probably a silicate mineral, which interferes with the quartz peak. Thus, the presence of cement leads to lower quartz values and brick leads to higher values, but overall, 83% of the quartz contents predicted from the calibration data agreed within 50% of the adjusted nominal loadings within the range 20-110 µg. This result is encouraging given the high levels of interfering dusts. Nine samples loaded with smaller amounts of all four dusts together gave results within 25% of the adjusted nominal loadings. A single mixture addition of the dusts to the filter gave tighter variance in results than sequential additions. Unexpectedly, the two Certified Reference Materials (CRMs) 1878a and 1878b, gave different results when used to calibrate XRD analysis of Min-u-Sil 5. |
Bioactivity of circulatory factors after pulmonary exposure to mild- and stainless-steel welding fumes
Kodali V , Shoeb M , Meighan TG , Eye T , Friend SA , Hubczak J , Kashon ML , Zeidler-Erdely PC , Antonini JM , Erdely A . Toxicol Sci 2020 177 (1) 108-120 Studies suggest that alterations in circulating factors are a driver of pulmonary-induced cardiovascular dysfunction. To evaluate if circulating factors effect endothelial function after a pulmonary exposure to welding fumes, an exposure known to induce cardiovascular dysfunction, serum collected from Sprague-Dawley rats 24 h after an intratracheal instillation exposure to 2 mg/rat of two compositionally distinct metal-rich welding fume particulates [manual metal arc welding using stainless steel electrodes (MMA-SS) or gas metal arc welding using mild steel electrodes (GMA-MS)] or saline was used to test molecular and functional effects of in vitro cultures of primary cardiac microvascular endothelial cells (PCME) or ex vivo organ cultures. The welding fumes elicited significant pulmonary injury and inflammation with only minor changes in measured serum antioxidant and cytokine levels. PCME cells were challenged for 4 h with serum collected from exposed rats, and 84 genes related to endothelial function were analyzed. Changes in relative mRNA patterns indicated that serum from rats exposed to MMA-SS, and not GMA-MS or PBS, could influence several functional aspects related to endothelial cells, including cell migration, angiogenesis, inflammation, and vascular function. The predictions were confirmed using a functional in vitro assay (scratch assay) as well as an ex vivo multicellular environment (aortic ring angiogenesis assay), validating the concept that endothelial cells can be used as an effective screening tool of exposed workers for determining bioactivity of altered circulatory factors. Overall, the results indicate that pulmonary MMA-SS fume exposure can cause altered endothelial function systemically via altered circulating factors. |
Evaluation of sorbent sampling and analysis procedures for acetone in workplace air: Variations of concentration and relative humidity
Soo JC , Lebouf RF , Chisholm WP , Nelson J , Roberts J , Kashon ML , Lee EG , Harper M . Ann Work Expo Health 2019 64 (1) 96-105 This study experimentally evaluates the performance of different sorbent tubes for sampling acetone vapor in workplace air. A dynamic atmosphere system produced an acetone alone and a mixture with other analytes containing ~73, 483, and 1898 microg acetone mass loading at 25, 50, and 75% relative humidity (RH) at 25 degrees C. Sorbent samples were analyzed in accordance with OSHA Method 69 (Carbosieve S-III) and NMAM 1501, modified to use Anasorb 747 sorbent. Both methods were modified to include the additional analytes. Additional extraction procedures with and without 1% dimethylformamide and anhydrous magnesium sulfate were included in the modified NMAM 1501 using Anasorb 747. Silica gel sorbent tubes analyzed according to NMAM 2027 were included. There were significant reductions in the recovery of acetone from both Anasorb 747 and Carbosieve S-III collected from air at 75% RH, relative to collection at 25 or 50% RH at very low loading compared with that of samples collected at mid to high loading. Silica gel provided a consistent recovery of acetone at all RHs and in the presence of other chemical interferences at 75% RH. The likely cause of mass dependence may arise from the humidity effect on acetone adsorption onto both beaded active carbon and carbon molecular sieve either in sampling or in analysis. The present study confirms not only previous observations but also adds to the literature showing carbonaceous sorbents are not well suited for sampling ketones at high humidity and low concentration. |
Mitsui-7, heat-treated, and nitrogen-doped multi-walled carbon nanotubes elicit genotoxicity in human lung epithelial cells
Siegrist KJ , Reynolds SH , Porter DW , Mercer RR , Bauer AK , Lowry D , Cena L , Stueckle TA , Kashon ML , Wiley J , Salisbury JL , Mastovich J , Bunker K , Sparrow M , Lupoi JS , Stefaniak AB , Keane MJ , Tsuruoka S , Terrones M , McCawley M , Sargent LM . Part Fibre Toxicol 2019 16 (1) 36 BACKGROUND: The unique physicochemical properties of multi-walled carbon nanotubes (MWCNT) have led to many industrial applications. Due to their low density and small size, MWCNT are easily aerosolized in the workplace making respiratory exposures likely in workers. The International Agency for Research on Cancer designated the pristine Mitsui-7 MWCNT (MWCNT-7) as a Group 2B carcinogen, but there was insufficient data to classify all other MWCNT. Previously, MWCNT exposed to high temperature (MWCNT-HT) or synthesized with nitrogen (MWCNT-ND) have been found to elicit attenuated toxicity; however, their genotoxic and carcinogenic potential are not known. Our aim was to measure the genotoxicity of MWCNT-7 compared to these two physicochemically-altered MWCNTs in human lung epithelial cells (BEAS-2B & SAEC). RESULTS: Dose-dependent partitioning of individual nanotubes in the cell nuclei was observed for each MWCNT material and was greatest for MWCNT-7. Exposure to each MWCNT led to significantly increased mitotic aberrations with multi- and monopolar spindle morphologies and fragmented centrosomes. Quantitative analysis of the spindle pole demonstrated significantly increased centrosome fragmentation from 0.024-2.4 mug/mL of each MWCNT. Significant aneuploidy was measured in a dose-response from each MWCNT-7, HT, and ND; the highest dose of 24 mug/mL produced 67, 61, and 55%, respectively. Chromosome analysis demonstrated significantly increased centromere fragmentation and translocations from each MWCNT at each dose. Following 24 h of exposure to MWCNT-7, ND and/or HT in BEAS-2B a significant arrest in the G1/S phase in the cell cycle occurred, whereas the MWCNT-ND also induced a G2 arrest. Primary SAEC exposed for 24 h to each MWCNT elicited a significantly greater arrest in the G1 and G2 phases. However, SAEC arrested in the G1/S phase after 72 h of exposure. Lastly, a significant increase in clonal growth was observed one month after exposure to 0.024 mug/mL MWCNT-HT & ND. CONCLUSIONS: Although MWCNT-HT & ND cause a lower incidence of genotoxicity, all three MWCNTs cause the same type of mitotic and chromosomal disruptions. Chromosomal fragmentation and translocations have not been observed with other nanomaterials. Because in vitro genotoxicity is correlated with in vivo genotoxic response, these studies in primary human lung cells may predict the genotoxic potency in exposed human populations. |
Survival of Staphylococcus aureus on the outer shell of fire fighter turnout gear after sanitation in a commercial washer/extractor
Farcas D , Blachere FM , Kashon ML , Sbarra D , Schwegler-Berry D , Stull JO , Noti JD . J Occup Med Toxicol 2019 14 (1) 10 Background: Methicillin-resistant Staphylococcus aureus contamination on surfaces including turnout gear had been found throughout a number of fire stations. As such, the outer shell barrier of turnout gear jackets may be an indirect transmission source and proper disinfection is essential to reduce the risk of exposure to fire fighters. Cleaning practices vary considerably among fire stations, and a method to assess disinfection of gear washed in commercial washer/extractors is needed. Methods: Swatches (1 in. × 1.5 in.) of the outer shell fabrics, Gemini™, Advance™, and Pioneer™, of turnout gear were inoculated with S. aureus, and washed with an Environmental Protection Agency-registered sanitizer commonly used to wash turnout gear. To initially assess the sanitizer, inoculated swatches were washed in small tubes according to the American Society for Testing Materials E2274 Protocol for evaluating laundry sanitizers. Inoculated swatches were also pinned to turnout gear jackets and washed in a Milnor commercial washer/extractor. Viable S. aureus that remained attached to fabric swatches after washing were recovered and quantified. Scanning Electron Microscopy was used to characterize the stages of S. aureus biofilm formation on the swatches that can result in resistance to disinfection. Results: Disinfection in small tubes for only 10 s reduced the viability of S. aureus on Gemini™, Advance™, and Pioneer™ by 73, 99, and 100%, respectively. In contrast, disinfection of S. aureus-contaminated Gemini™ swatches pinned to turnout gear and washed in the washer/extractor was 99.7% effective. Scanning Electron Microscopy showed that biofilm formation begins as early as 5 h after attachment of S. aureus. Conclusion: This sanitizer and, likely, others containing the anti-microbial agent didecyl dimethyl ammonium chloride, is an effective disinfectant of S. aureus. Inclusion of contaminated outer shell swatches in the wash cycle affords a simple and quantitative method to assess sanitization of gear by commercial gear cleaning facilities. This methodology can be extended to assess for other bacterial contaminants. Sanitizer-resistant strains will continue to pose problems, and biofilm formation may affect the cleanliness of the washed turnout gear. Our methodology for assessing effectiveness of disinfection may help reduce the occupational exposure to fire fighters from bacterial contaminants. |
Reduced frequency of resistance-type exercise training promotes adaptation of the aged skeletal muscle microenvironment
Naimo MA , Rader EP , Ensey J , Kashon ML , Baker BA . J Appl Physiol (1985) 2019 126 (4) 1074-1087 The purpose of this study was to characterize the growth and remodeling molecular signaling response in aged skeletal muscle following one month of "resistance-type exercise" training. Male Fisher344x Brown Norway hybrid rats aged 3 (young) and 30 months (old) underwent stretch-shortening contraction (SSC) loading two or three days per week; muscles were removed 72 hours post-training. Young rats SSC-loaded three (Y3x) or two days per week (Y2x) adapted via increased work performance. Old rats SSC-loaded three days per week (O3x) maladapted via decreased negative work; however, old rats SSC-loaded two days per week (O2x) adapted through improved negative and positive work. Y3x, Y2x, and O2x, but not O3x, displayed hypertrophy via larger fiber area and myonuclear domains. Y3x, Y2x, and O2x differentially expressed 19, 30, and 8 PI3K-AKT genes, respectively, whereas O3x only expressed two. Bioinformatics analysis revealed that rats in the adapting groups presented growth and remodeling processes (i.e. increased protein synthesis), whereas O3x demonstrated inflammatory signaling. In conclusion, reducing SSC-loading frequency in aged rodents positively influences the molecular signaling microenvironment, promoting muscle adaptation. |
Performance evaluation of disposable inhalable aerosol sampler at a copper electrorefinery
Lee EG , Grimson PJ , Chisholm WP , Kashon ML , He X , L'Orange C , Volckens J . J Occup Environ Hyg 2019 16 (3) 1-10 This study evaluates the performance of the disposable inhalable aerosol sampler (DIAS), a new sampler developed to be more cost-effective than the traditional inhalable particle samplers and comparable to the inhalable particle sampling convention. Forty-eight pairs of the DIAS prototype and the IOM sampler were utilized to collect copper exposure measurements (23 personal and 25 area) at an electrorefinery facility. The geometric mean (GM) value of ratios of exposure data (DIAS/IOM) was 1.1, while the GM of ratios (DIAS/IOM) was 1.6 for the area exposure data, revealing 84%of the ratios were greater than one. For both personal and area exposure data, the concordance correlation coefficient tests revealed significant disagreements between the two types of samplers and suggested precision as the source of the disagreement. The estimated mean concentration was higher for the DIAS compared that for the IOM for the area exposure data (p < 0.05), while the results were comparable for the personal exposure data (p = 0.49). Overall, the DIAS generated higher exposure results compared to the IOM sampler for the area exposures. For the personal exposures, the findings were inconclusive due to inconsistent results of factors aforementioned. This study is limited to one metal component (copper) of the dust at a worksite. To date, this is the first field evaluation using personal exposure data to test the performance of the DIAS and the second evaluation using area exposure data. Thus, it will be necessary to conduct additional field evaluations with various elements to further evaluate the performance of the DIAS. In addition, particle migration to the internal walls of the cap was observed during the transportation of collected samples to a laboratory for both sampler types (6.4% for the DIAS and 7.4% for the IOM). Occupational health and safety professionals should be aware of potential errors caused from transferring samples from a field to a laboratory and should be careful not to exclude particles collected on the caps. |
Topical application of the quaternary ammonium compound didecyldimethylammonium chloride activates type 2 innate lymphoid cells and initiates a mixed-type allergic response
Shane HL , Lukomska E , Kashon ML , Anderson SE . Toxicol Sci 2019 168 (2) 508-518 Didecyldimethylammonium chloride (DDAC) is an antimicrobial dialkyl-quaternary ammonium compound used in industrial and commercial products. Clinical data suggest that DDAC exposure elicits multiple types of hypersensitivity reactions; here, we confirm this observation in a BALB/c murine model. To examine the immunological mechanism behind this mixed-type response and the potential involvement of type 2 innate lymphoid cells (ILC2s), we assessed early immune responses in the skin following topical DDAC exposure (0.125% and 0.5%). DDAC exposure resulted in a rapid and dramatic increase in the Th2-skewing and ILC2 activating cytokine thymic stromal lymphopoietin. Correspondingly, dermal ILC2s were activated 24 hours after DDAC exposure, resulting in increased expression of CD25, ICOS and KLRG1, and decreased CD127 throughout 7 days of exposure. Following ILC2 activation, the Th2 cytokine IL-4 was elevated compared to control mice in total ear protein lysate (0.5% DDAC). Rag2-/- mice were used to determine a functional role for ILC2s in DDAC induced sensitization. ILC2s from Rag2-/- mice were similarly activated by DDAC and, importantly, produced significant levels of IL-4 and IL-5 in the skin (0.5% DDAC). These data indicate that ILC2s contribute to early Th2 immune responses following DDAC exposure. ILC2s have been previously implicated in allergic responses, but to our knowledge have not been thoroughly investigated in chemical sensitization. These results indicate that following DDAC exposure, skin ILC2s become activated and produce Th2 cytokines, providing a possible mechanism for the development of the mixed-type allergic responses commonly observed with chemical sensitizers. |
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