Publications (66)223.22 Total impact
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Article: Adjuvant effect of zymosan after pulmonary treatment in a mouse ovalbumin allergy model.
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ABSTRACT: ABSTRACT An association has been observed between indoor mold contamination and lung allergy and asthma. This relationship is not fully understood. 1→3-β-Glucan is the major cell wall component of fungi and a good marker of fungi exposure. The objective was to evaluate the adjuvant effect of zymosan, a crude yeast cell wall preparation of 1→3-β-glucan, during ovalbumin (OVA) sensitization in an allergy model. BALB/c mice were sensitized by pharyngeal aspiration with saline, 50 μg of OVA, or OVA with 1, 10, 50, or 75 μg of zymosan on days 0, 7, and 14. One week after sensitization, each sensitized animal group was challenged with an aspiration dose of 50 μg of OVA once a week for 2 weeks. At 1 day after the last aspiration, bronchoalveolar lavage fluid and blood was collected, and markers of lung allergy and inflammation were assessed. An adjuvant effect of zymosan on OVA allergy during sensitization was observed as indicated by significant elevations in lung eosinophils, serum OVA-specific IgE, and lung IL-5 in the groups sensitized with zymosan and OVA. Pulmonary treatment with zymosan also amplified lung inflammation. Elevations were observed in lung neutrophils, TNF-α, and parameters of lung injury in the groups primed with both zymosan and OVA. In nearly all parameters, a non-linear dose-response relationship was observed in the groups primed with OVA and zymosan. The optimum adjuvant dose of zymosan was 10 μg. This study demonstrated an adjuvant effect of zymosan when exposures occurred during the sensitization phase in an OVA-induced allergy model in BALB/c mice.Experimental Lung Research 01/2013; · 1.22 Impact Factor -
Article: Lung toxicity and biodistribution of Cd/Se-ZnS quantum dots with different surface functional groups after pulmonary exposure in rats.
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ABSTRACT: The potential use of quantum dots (QD) in biomedical applications, as well as in other systems that take advantage of their unique physiochemical properties, has led to concern regarding their toxicity, potential systemic distribution, and biopersistence. In addition, little is known about workplace exposure to QD in research, manufacturing, or medical settings. The goal of the present study was to assess pulmonary toxicity, clearance, and biodistribution of QD with different functional groups in rats after pulmonary exposure. QD were composed of a cadmium-selenide (CdSe) core (~5nm) with a zinc sulfide (ZnS) shell functionalized with carboxyl (QD-COOH) or amine (QD-NH2) terminal groups. Male Sprague-Dawley rats were intratracheally-instilled (IT) with saline, QD-COOH, or QD-NH2 (12.5, 5.0, or 1.25 μg/rat). On days 0, 1, 3, 5, 7, 14, and 28 post-IT, the left lung, lung-associated lymph nodes (LALN), heart, kidneys, spleen, liver, brain, and blood were collected for metal analysis of Cd content by neutron activation to evaluate clearance and biodistribution. One right lobe was ligated and fixed for microscopy and histopathological analysis. The remaining right lobes from rats in each group were subjected to bronchoalveolar lavage (BAL) to retrieve BAL fluid and cells for analysis of injury and inflammation. Lung injury and inflammation was found to be dose-dependent and peaked at days 7 and 14 post-exposure for both forms of QD, with slight variations in degree of toxicity at early and later time points. Both QD appeared to lose their fluorescent properties and destabilize after 1 week in the lung. Cd persisted up to 28 days for both forms of QD; however, clearance rate was slightly greater for QD-COOH over time. No Cd was detected in the liver, spleen, heart, brain, or blood at any time point. Cd appeared in the LALN and kidneys beginning at 1-2 weeks post-exposure. QD-COOH and QD-NH2 differed in clearance rate and differed slightly in degree of toxicity at different time points; however, the overall pattern of toxicity and biodistribution was similar between the two particles. Toxicity may be dependent on the dissolution rate and bioavailability of free Cd.Particle and Fibre Toxicology 01/2013; 10:5. · 7.25 Impact Factor -
Article: Type I interferon and pattern recognition receptor signaling following particulate matter inhalation.
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ABSTRACT: BACKGROUND: Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc - stainless steel (GMA-SS) welding fume at 40mg/m3 for 3hr/d for 10d and sacrificed 4hr, 14d and 28d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. RESULTS: The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon alpha and beta and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS. Conclusion: This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure.Particle and Fibre Toxicology 07/2012; 9(1):25. · 7.25 Impact Factor -
Article: Immunotoxicology of arc welding fume: Worker and experimental animal studies.
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ABSTRACT: Arc welding processes generate complex aerosols composed of potentially hazardous metal fumes and gases. Millions of workers worldwide are exposed to welding aerosols daily. A health effect of welding that is of concern to the occupational health community is the development of immune system dysfunction. Increased severity, frequency, and duration of upper and lower respiratory tract infections have been reported among welders. Specifically, multiple studies have observed an excess mortality from pneumonia in welders and workers exposed to metal fumes. Although several welder cohort and experimental animal studies investigating the adverse effects of welding fume exposure on immune function have been performed, the potential mechanisms responsible for these effects are limited. The objective of this report was to review both human and animal studies that have examined the effect of welding fume pulmonary exposure on local and systemic immune responses.Journal of Immunotoxicology 06/2012; · 1.44 Impact Factor -
Article: Systemic immune cell response in rats after pulmonary exposure to manganese-containing particles collected from welding aerosols.
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ABSTRACT: Welding fume inhalation affects the immune system of exposed workers. Manganese (Mn) in welding fume may induce immunosuppressive effects. The goal was to determine if Mn in welding fume alters immunity by reducing the number of circulating total leukocytes and specific leukocyte sub-populations. Sprague-Dawley rats were treated by intratracheal instillation (ITI) with either a single dose (2.00 mg/rat) or repeated doses (0.125 or 2.00 mg/rat for 7 weeks) with welding fumes that contained different levels of Mn. Additional rats were treated by ITI once a week for 7 weeks with the two doses of manganese chloride (MnCl₂). Bronchoalveolar lavage was performed to assess lung inflammation. Also, whole blood was recovered, and the number of circulating total leukocytes, as well as specific lymphocyte subsets, was determined by flow cytometry. The welding fume highest in Mn content significantly increased lung inflammation, injury, and production of inflammatory cytokines and chemokines compared to all other treatment groups. In addition, the same group expressed significant decreases in the number of circulating CD4⁺ and CD8⁺ T-lymphocytes after a single exposure, and significant reductions in the number of circulating total lymphocytes, primarily CD4⁺ and CD8⁺ T-lymphocytes, after repeated exposures (compared to control values). Repeated MnCl₂ exposure led to a trend of a reduction (but not statistically significant) in circulating total lymphocytes, attributable to the changes in the CD4⁺ T-lymphocyte population levels. The welding fume with the lower concentration of Mn had no significant effect on the numbers of blood lymphocytes and lymphocyte subsets compared to control values. Evidence from this study indicates that pulmonary exposure to certain welding fumes cause decrements in systemic immune cell populations, specifically circulating T-lymphocytes, and these alterations in immune cell number are not dependent exclusively on Mn, but likely a combination of other metals present in welding fume.Journal of Immunotoxicology 02/2012; 9(2):184-92. · 1.44 Impact Factor -
Article: Manganese accumulation in nail clippings as a biomarker of welding fume exposure and neurotoxicity.
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ABSTRACT: Occupational exposure to welding fumes (WF) is thought to cause Parkinson's disease (PD)-like neurological dysfunction. An apprehension that WF may accelerate the onset of PD also exists. Identifying reliable biomarkers of exposure and neurotoxicity are therefore critical for biomonitoring and neurological risk characterization of WF exposure. Manganese (Mn) in welding consumables is considered the causative factor for the neurological deficits seen in welders. Hence, we sought to determine if Mn accumulation in blood or nail clippings can be a marker for adverse exposure and neurotoxicity. To model this, rats were exposed by intratracheal instillation to dissolved or suspended fume components collected from gas metal arc-mild steel (GMA-MS) or manual metal arc-hard surfacing (MMA-HS) welding. Trace element analysis revealed selective Mn accumulation in dopaminergic brain areas, striatum (STR) and midbrain (MB), following exposure to the two fumes. This caused dopaminergic abnormality as evidenced by loss of striatal tyrosine hydroxylase (Th; 25-32% decrease) and Parkinson disease (autosomal recessive, early onset) 7 (Park7; 25-46% decrease) proteins. While blood Mn was not detectable, Mn levels in nails strongly correlated with the pattern of Mn accumulation in the striatum (R(2)=0.9386) and midbrain (R(2)=0.9332). Exposure to manganese chloride (MnCl(2)) caused similar Mn accumulation in STR, MB and nail. Our findings suggest that nail Mn has the potential to be a sensitive and reliable biomarker for long-term Mn exposure and associated neurotoxicity. The non-invasive means by which nail clippings can be collected, stored, and transported with relative ease, make it an attractive surrogate for biomonitoring WF exposures in occupational settings.Toxicology 11/2011; 291(1-3):73-82. · 3.68 Impact Factor -
Article: Inhalation exposure of gas-metal arc stainless steel welding fume increased atherosclerotic lesions in apolipoprotein E knockout mice.
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ABSTRACT: Epidemiological studies suggest that welding, a process which generates an aerosol of inhalable gases and metal rich particulates, increases the risk for cardiovascular disease. In this study we analyzed systemic inflammation and atherosclerotic lesions following gas metal arc-stainless steel (GMA-SS) welding fume exposure. Apolipoprotein E knockout (apoE(-/-)) mice, fed a Western diet, were exposed to GMA-SS at 40mg/m(3) for 3h/day for ten days (∼8.26μg daily alveolar deposition). Mice were sacrificed two weeks after exposure and serum chemistry, serum protein profiling and aortic lesion area were determined. There were no significant changes in serum total cholesterol, triglycerides or alanine aminotransferase. Serum levels of uric acid, a potent antioxidant, were decreased perhaps suggesting a reduced capacity to combat systemic oxidative stress. Inflammatory serum proteins interleukin 1 beta (IL-1β) and monocyte chemoattractant protein 3 (MCP-3) were increased two weeks after GMA-SS exposure. Analysis of atherosclerotic plaques showed an increase in lesion area as the result of GMA-SS exposure. In conclusion, GMA-SS exposure showed evidence of systemic inflammation and increased plaque progression in apoE(-/-) mice. These results complement epidemiological and functional human studies that suggest welding may result in adverse cardiovascular effects.Toxicology Letters 07/2011; 204(1):12-6. · 3.23 Impact Factor -
Article: Relationship between pulmonary and systemic markers of exposure to multiple types of welding particulate matter.
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ABSTRACT: Welding results in a unique and complex occupational exposure. Recent epidemiological studies have shown an increased risk of cardiovascular disease following welding fume exposure. In this study, we compared the induction of pulmonary and systemic inflammation following exposure to multiple types of welding fumes. Mice were exposed to 340μg of manual metal arc stainless steel (MMA-SS), gas metal arc-SS (GMA-SS) or GMA-mild steel (GMA-MS) by pharyngeal aspiration. Mice were sacrificed at 4 and 24h post-exposure to evaluate various parameters of pulmonary and systemic inflammation. Alterations in pulmonary gene expression by a custom designed TaqMan array showed minimal differences between the fumes at 4h. Conversely at 24h, gene expression changes were further increased by SS but not GMA-MS exposure. These findings were associated with the surrogate marker of systemic inflammation, liver acute phase gene induction. Interestingly, stress response genes in cardiovascular tissues were only increased following MMA-SS exposure. These effects were related to the initial level of pulmonary cytotoxicity, as measured by lactate dehydrogenase activity, which was greatest following MMA-SS exposure. In conclusion, varying types of welding fumes elicit quantitatively different systemic inflammatory and/or stress responses.Toxicology 06/2011; 287(1-3):153-9. · 3.68 Impact Factor -
Article: Alterations in welding process voltage affect the generation of ultrafine particles, fume composition, and pulmonary toxicity.
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ABSTRACT: The goal was to determine if increasing welding voltage changes the physico-chemical properties of the fume and influences lung responses. Rats inhaled 40 mg/m³ (3 h/day × 3 days) of stainless steel (SS) welding fume generated at a standard voltage setting of 25 V (regular SS) or at a higher voltage (high voltage SS) of 30 V. Particle morphology, size and composition were characterized. Bronchoalveolar lavage was performed at different times after exposures to assess lung injury. Fumes collected from either of the welding conditions appeared as chain-like agglomerates of nanometer-sized primary particles. High voltage SS welding produced a greater number of ultrafine-sized particles. Fume generated by high voltage SS welding was higher in manganese. Pulmonary toxicity was more substantial and persisted longer after exposure to the regular SS fume. In summary, a modest raise in welding voltage affected fume size and elemental composition and altered the temporal lung toxicity profile.Nanotoxicology 02/2011; 5(4):700-10. · 5.76 Impact Factor -
Article: Short-term inhalation of stainless steel welding fume causes sustained lung toxicity but no tumorigenesis in lung tumor susceptible A/J mice.
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ABSTRACT: Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at-risk population for development of lung cancer. Our objective was to expose, by inhalation, lung tumor susceptible (A/J) and resistant C57BL/6J (B6) mice to stainless steel (SS) welding fume containing carcinogenic metals and characterize the lung-inflammatory and tumorigenic response. Male mice were exposed to air or gas metal arc (GMA)-SS welding fume at 40 mg/m(3)×3 h/day for 6 and 10 days. At 1, 4, 7, 10, 14, and 28 days after 10 days of exposure, bronchoalveolar lavage (BAL) was done. Lung cytotoxicity, permeability, inflammatory cytokines, and cell differentials were analyzed. For the lung tumor study, gross tumor counts and histopathological changes were assessed in A/J mice at 78 weeks after 6 and 10 days of exposure. Inhalation of GMA-SS fume caused an early, sustained macrophage and lymphocyte response followed by a gradual neutrophil influx and the magnitudes of these differed between the mouse strains. Monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNF-α) were increased in both strains while the B6 also had increased interleukin-6 (IL-6) protein. BAL measures of cytotoxicity and damage were similar between the strains and significantly increased at all time points. Histopathology and tumorigenesis were unremarkable at 78 weeks. In conclusion, GMA-SS welding fume induced a significant and sustained inflammatory response in both mouse strains with no recovery by 28 days. Under our exposure conditions, GMA-SS exposure resulted in no significant tumor development in A/J mice.Inhalation Toxicology 02/2011; 23(2):112-20. · 1.92 Impact Factor -
Article: Toxicological evaluation of lung responses after intratracheal exposure to non-dispersed titanium dioxide nanorods.
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ABSTRACT: Fine- and coarse-sized titanium dioxide (TiO₂) particles are considered to be relatively inert when inhaled. The goal of this study was to assess potential lung toxicity associated with well-characterized, non-dispersed rutile TiO₂ nanorods (10 × 40 nm). In vitro bioreactivity of TiO₂ nanorods was determined by electron spin resonance (ESR) to measure free radical production. To assess pulmonary effects in vivo, Sprague-Dawley rats were intratracheally instilled with saline, silica, or TiO₂ nanorods (10 μg, 100 μg, or 1 mg/rat). On d 1, 3, and 6 posttreatment, left lungs were preserved for microscopy and histopathology, and lung lavage was performed on right lungs. Additional rats were treated with saline or TiO₂ nanorods (100 μg or 1 mg/rat) on d 0, intratracheally inoculated with 5 × 10(5) Listeria monocytogenes on d 3, and bacterial clearance was assessed. ESR showed a significant concentration-dependent generation of hydroxyl radicals by TiO₂ nanorods in the presence and absence of macrophages; however, the hydroxyl radical signals from TiO₂ samples were low compared to silica. Rats exposed to 1 mg of TiO₂ nanorods had significantly elevated levels of lung injury, inflammation, and lavage fluid monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 on d 1 and 3 that subsided by d 6, unlike the silica response that persisted. Immune cytokine secretion in the lung and bacterial clearance were not affected by preexposure to TiO₂ nanorods. To summarize, non-dispersed TiO₂ nanorods were found to induce radical formation and cellular oxidant production, and to generate transient and reversible pneumotoxic effects, and to not markedly alter pulmonary immune function.Journal of Toxicology and Environmental Health Part A 01/2011; 74(12):790-810. · 1.83 Impact Factor -
Article: Lung tumor production and tissue metal distribution after exposure to manual metal ARC-stainless steel welding fume in A/J and C57BL/6J mice.
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ABSTRACT: Stainless steel welding produces fumes that contain carcinogenic metals. Therefore, welders may be at risk for the development of lung cancer, but animal data are inadequate in this regard. Our main objective was to examine lung tumor production and histopathological alterations in lung-tumor-susceptible (A/J) and -resistant C57BL/6J (B6) mice exposed to manual metal arc-stainless steel (MMA-SS) welding fume. Male mice were exposed to vehicle or MMA-SS welding fume (20 mg/kg) by pharyngeal aspiration once per month for 4 mo. At 78 wk postexposure, gross tumor counts and histopathological changes were assessed and metal analysis was done on extrapulmonary tissue (aorta, heart, kidney, and liver). At 78 wk postexposure, gross lung tumor multiplicity and incidence were unremarkable in mice exposed to MMA-SS welding fume. Histopathology revealed that only the exposed A/J mice contained minimal amounts of MMA-SS welding fume in the lung and statistically increased lymphoid infiltrates and alveolar macrophages. A significant increase in tumor multiplicity in the A/J strain was observed at 78 wk. Metal analysis of extrapulmonary tissue showed that only the MMA-SS-exposed A/J mice had elevated levels of Cr, Cu, Mn, and Zn in kidney and Cr in liver. In conclusion, this study further supports that MMA-SS welding fume does not produce a significant tumorigenic response in an animal model, but may induce a chronic lung immune response. In addition, long-term extrapulmonary tissue alterations in metals in the susceptible A/J mouse suggest that the adverse effects of this fume might be cumulative.Journal of Toxicology and Environmental Health Part A 01/2011; 74(11):728-36. · 1.83 Impact Factor -
Article: Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes.
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ABSTRACT: Welding generates complex metal aerosols, inhalation of which is linked to adverse health effects among welders. An important health concern of welding fume (WF) exposure is neurological dysfunction akin to Parkinson's disease (PD), thought to be mediated by manganese (Mn) in the fumes. Also, there is a proposition that welding might accelerate the onset of PD. Our recent findings link the presence of Mn in the WF with dopaminergic neurotoxicity seen in rats exposed to manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) fumes. To elucidate the molecular mechanisms further, we investigated the association of PD-linked (Park) genes and mitochondrial function in causing dopaminergic abnormality. Repeated instillations of the two fumes at doses that mimic ∼1 to 5 yr of worker exposure resulted in selective brain accumulation of Mn. This accumulation caused impairment of mitochondrial function and loss of tyrosine hydroxylase (TH) protein, indicative of dopaminergic injury. A fascinating finding was the altered expression of Parkin (Park2), Uchl1 (Park5), and Dj1 (Park7) proteins in dopaminergic brain areas. A similar regimen of manganese chloride (MnCl(2)) also caused extensive loss of striatal TH, mitochondrial electron transport components, and Park proteins. As mutations in PARK genes have been linked to early-onset PD in humans, and because welding is implicated as a risk factor for parkinsonism, PARK genes might play a critical role in WF-mediated dopaminergic dysfunction. Whether these molecular alterations culminate in neurobehavioral and neuropathological deficits reminiscent of PD remains to be ascertained.The FASEB Journal 12/2010; 24(12):4989-5002. · 5.71 Impact Factor -
Article: Comparison of stainless and mild steel welding fumes in generation of reactive oxygen species.
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ABSTRACT: Welding fumes consist of a wide range of complex metal oxide particles which can be deposited in all regions of the respiratory tract. The welding aerosol is not homogeneous and is generated mostly from the electrode/wire. Over 390,000 welders were reported in the U.S. in 2008 while over 1 million full-time welders were working worldwide. Many health effects are presently under investigation from exposure to welding fumes. Welding fume pulmonary effects have been associated with bronchitis, metal fume fever, cancer and functional changes in the lung. Our investigation focused on the generation of free radicals and reactive oxygen species from stainless and mild steel welding fumes generated by a gas metal arc robotic welder. An inhalation exposure chamber located at NIOSH was used to collect the welding fume particles. Our results show that hydroxyl radicals (.OH) were generated from reactions with H2O2 and after exposure to cells. Catalase reduced the generation of .OH from exposed cells indicating the involvement of H2O2. The welding fume suspension also showed the ability to cause lipid peroxidation, effect O2 consumption, induce H2O2 generation in cells, and cause DNA damage. Increase in oxidative damage observed in the cellular exposures correlated well with .OH generation in size and type of welding fumes, indicating the influence of metal type and transition state on radical production as well as associated damage. Our results demonstrate that both types of welding fumes are able to generate ROS and ROS-related damage over a range of particle sizes; however, the stainless steel fumes consistently showed a significantly higher reactivity and radical generation capacity. The chemical composition of the steel had a significant impact on the ROS generation capacity with the stainless steel containing Cr and Ni causing more damage than the mild steel. Our results suggest that welding fumes may cause acute lung injury. Since type of fume generated, particle size, and elapsed time after generation of the welding exposure are significant factors in radical generation and particle deposition these factors should be considered when developing protective strategies.Particle and Fibre Toxicology 11/2010; 7:32. · 7.25 Impact Factor -
Article: Persistence of deposited metals in the lungs after stainless steel and mild steel welding fume inhalation in rats.
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ABSTRACT: Welding generates complex metal fumes that vary in composition. The objectives of this study were to compare the persistence of deposited metals and the inflammatory potential of stainless and mild steel welding fumes, the two most common fumes used in US industry. Sprague-Dawley rats were exposed to 40 mg/m(3) of stainless or mild steel welding fumes for 3 h/day for 3 days. Controls were exposed to filtered air. Generated fume was collected, and particle size and elemental composition were determined. Bronchoalveolar lavage was done on days 0, 8, 21, and 42 after the last exposure to assess lung injury/inflammation and to recover lung phagocytes. Non-lavaged lung samples were analyzed for total and specific metal content as a measure of metal persistence. Both welding fumes were similar in particle morphology and size. Following was the chemical composition of the fumes-stainless steel: 57% Fe, 20% Cr, 14% Mn, and 9% Ni; mild steel: 83% Fe and 15% Mn. There was no effect of the mild steel fume on lung injury/inflammation at any time point compared to air control. Lung injury and inflammation were significantly elevated at 8 and 21 days after exposure to the stainless steel fume compared to control. Stainless steel fume exposure was associated with greater recovery of welding fume-laden macrophages from the lungs at all time points compared with the mild steel fume. A higher concentration of total metal was observed in the lungs of the stainless steel welding fume at all time points compared with the mild steel fume. The specific metals present in the two fumes were cleared from the lungs at different rates. The potentially more toxic metals (e.g., Mn, Cr) present in the stainless steel fume were cleared from the lungs more quickly than Fe, likely increasing their translocation from the respiratory system to other organs.Archive für Toxikologie 10/2010; 85(5):487-98. · 4.67 Impact Factor -
Article: Pulmonary toxicity and extrapulmonary tissue distribution of metals after repeated exposure to different welding fumes.
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ABSTRACT: Welders are exposed to fumes with different metal profiles. The goals of this study were to compare lung responses in rats after treatment with chemically different welding fumes and to examine the extrapulmonary fate of metals after deposition in the lungs. Rats were treated by intratracheal instillation (0.5 mg/rat, once a week for 7 weeks) with gas metal arc-mild steel (GMAW-MS) or manual metal arc-hardsurfacing (MMAW-HS) welding fumes. Controls were treated with saline. At 1, 4, 35, and 105 days after the last treatment, lung injury and inflammation were measured, and elemental analysis of different organs was determined to assess metal clearance. The MMAW-HS fume was highly water-soluble and chemically more complex with higher levels of soluble Mn and Cr compared to the GMAW-MS fume. Treatments with the GMAW-MS fume had no effect on toxicity when compared with controls. The MMAW-HS fume induced significant lung damage early after treatment that remained elevated until 35 days. Metals associated with each fume sample was cleared at different rates from the lungs. Mn was cleared from the lungs at a faster rate and to a greater extent compared to the other metals over the 105-day recovery period. Mn and Cr in the MMAW-HS fume translocated from the respiratory tract and deposited in other organs. Importantly, increased deposition of Mn, but not other metals, was observed in discrete brain regions, including dopamine-rich areas (e.g., striatum and midbrain).Inhalation Toxicology 08/2010; 22(10):805-16. · 1.92 Impact Factor -
Article: Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes.
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ABSTRACT: The potential for development of Parkinson's disease (PD)-like neurological dysfunction following occupational exposure to aerosolized welding fumes (WF) is an area of emerging concern. Welding consumables contain a complex mixture of metals, including iron (Fe) and manganese (Mn), which are known to be neurotoxic. To determine whether WF exposure poses a neurological risk particularly to the dopaminergic system, we treated Sprague-Dawley rats with WF particulates generated from two different welding processes, gas metal arc-mild steel (GMA-MS; low Mn, less water-soluble) and manual metal arc-hard surfacing (MMA-HS; high Mn, more water-soluble) welding. Following repeated intratracheal instillations (0.5 mg/rat, 1/week x 7 weeks) of GMA-MS or MMA-HS, elemental analysis and various molecular indices of neurotoxicity were measured at 1, 4, 35 or 105 days after last exposure. MMA-HS exposure, in particular, led to increased deposition of Mn in striatum and midbrain. Both fumes also caused loss of tyrosine hydroxylase (TH) protein in the striatum (~20%) and midbrain (~30%) by 1 day post-exposure. While the loss of TH following GMA-MS was transient, a sustained loss (34%) was observed in the midbrain 105 days after cessation of MMA-HS exposure. In addition, both fumes caused persistent down-regulation of dopamine D2 receptor (Drd2; 30-40%) and vesicular monoamine transporter 2 (Vmat2; 30-55%) mRNAs in the midbrain. WF exposure also modulated factors associated with synaptic transmission, oxidative stress, neuroinflammation and gliosis. Collectively, our findings demonstrate that repeated exposure to Mn-containing WF can cause persistent molecular alterations in dopaminergic targets. Whether such perturbations will lead to PD-like neuropathological manifestations remains to be elucidated.Archive für Toxikologie 03/2010; 84(7):521-40. · 4.67 Impact Factor -
Article: Response of the mouse lung transcriptome to welding fume: effects of stainless and mild steel fumes on lung gene expression in A/J and C57BL/6J mice.
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ABSTRACT: Debate exists as to whether welding fume is carcinogenic, but epidemiological evidence suggests that welders are an at risk population for the development of lung cancer. Recently, we found that exposure to welding fume caused an acutely greater and prolonged lung inflammatory response in lung tumor susceptible A/J versus resistant C57BL/6J (B6) mice and a trend for increased tumor incidence after stainless steel (SS) fume exposure. Here, our objective was to examine potential strain-dependent differences in the regulation and resolution of the lung inflammatory response induced by carcinogenic (Cr and Ni abundant) or non-carcinogenic (iron abundant) metal-containing welding fumes at the transcriptome level. Mice were exposed four times by pharyngeal aspiration to 5 mg/kg iron abundant gas metal arc-mild steel (GMA-MS), Cr and Ni abundant GMA-SS fume or vehicle and were euthanized 4 and 16 weeks after the last exposure. Whole lung microarray using Illumina Mouse Ref-8 expression beadchips was done. Overall, we found that tumor susceptibility was associated with a more marked transcriptional response to both GMA-MS and -SS welding fumes. Also, Ingenuity Pathway Analysis revealed that gene regulation and expression in the top molecular networks differed between the strains at both time points post-exposure. Interestingly, a common finding between the strains was that GMA-MS fume exposure altered behavioral gene networks. In contrast, GMA-SS fume exposure chronically upregulated chemotactic and immunomodulatory genes such as CCL3, CCL4, CXCL2, and MMP12 in the A/J strain. In the GMA-SS-exposed B6 mouse, genes that initially downregulated cellular movement, hematological system development/function and immune response were involved at both time points post-exposure. However, at 16 weeks, a transcriptional switch to an upregulation for neutrophil chemotactic genes was found and included genes such as S100A8, S100A9 and MMP9. Collectively, our results demonstrate that lung tumor susceptibility may predispose the A/J strain to a prolonged dysregulation of immunomodulatory genes, thereby delaying the recovery from welding fume-induced lung inflammation. Additionally, our results provide unique insight into strain- and welding fume-dependent genetic factors involved in the lung response to welding fume.Respiratory research 01/2010; 11:70. · 3.36 Impact Factor -
Article: Mild steel welding fume causes manganese accumulation and subtle neuroinflammatory changes but not overt neuronal damage in discrete brain regions of rats after short-term inhalation exposure
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ABSTRACT: Serious questions have been raised by occupational health investigators regarding a possible causal association between neurological effects in welders and the presence of manganese (Mn) in welding fume. Male Sprague–Dawley rats were exposed by inhalation to 40 mg/m3 of gas metal arc-mild steel (MS) welding fume for 3 h/day for 10 days. Generated fume was collected in the animal chamber during exposure, and particle size, composition, and morphology were characterized. At 1 day after the last exposure, metal deposition in different organ systems and neurological responses in dopaminergic brain regions were assessed in exposed animals. The welding particles were composed primarily of a complex of iron (Fe) and Mn and were arranged as chain-like aggregates with a significant number of particles in the nanometer size range. Mn was observed to translocate from the lungs to the kidney and specific brain regions (olfactory bulb, cortex, and cerebellum) after MS fume inhalation. In terms of neurological responses, short-term MS fume inhalation induced significant elevations in divalent metal ion transporter 1 (Dmt1) expression in striatum and midbrain and significant increases in expression of proinflammatory chemokines (Ccl2, Cxcl2) and cytokines (IL1β, TNFα) in striatum. In addition, mRNA and protein expression of glial fibrillary acidic protein (GFAP) was significantly increased in striatum after MS fume exposure. However, the 10-day MS welding fume inhalation did not cause any changes in dopamine and its metabolites or GABA in dopaminergic brain regions nor did it produce overt neural cell damage as assessed by histopathology. In summary, short-term MS welding fume exposure led to translocation of Mn to specific brain regions and induced subtle changes in cell markers of neuroinflammatory and astrogliosis. The neurofunctional significance of these findings currently is being investigated in longer, more chronic welding fume exposure studies.NeuroToxicology 09/2009; · 3.10 Impact Factor -
Article: Preexposure to repeated low doses of zymosan increases the susceptibility to pulmonary infection in rats.
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ABSTRACT: Chronic exposure to low levels of mold has been reported to increase susceptibility to respiratory infections. In the current study, the authors investigate the lungs' ability to clear an infection after repeated low-dose zymosan exposure. Exposure was conducted at a zymosan dose of 0.6 mg/kg body weight (bw) of rat, for a total of 4 doses, via intratracheal instillation during a 2 week period. Treated animals were allowed to recover for 1 week before pulmonary inoculation with Listeria monocytogenes. Bacterial clearance was determined by measuring colony-forming units cultured from the left lungs on days 3, 5, and 7 post bacteria infection. Bronchoalveolar lavage (BAL) was performed on the right lungs to recover phagocytes and BAL fluid to measure lung injury and the inflammatory cytokines. In contrast to the authors' previously published study that showed a single high dose (2.5 mg/kg bw) of zymosan prior to infection accelerated bacteria clearance, the repeated low-dose zymosan suppressed bacteria clearance from the lungs early after infection and induced higher lung injury and inflammation compared to control. The innate immune response was down-regulated and a Th2 immune response was preferentially induced rather than a Th1 response, the latter being more effective toward the resolution of a L. monocytogenes infection.Experimental Lung Research 09/2009; 35(7):570-90. · 1.22 Impact Factor
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Institutions
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2013
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Kenya Centers for Disease Control and Prevention
Kisumu, Nyanza Province, Kenya
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2002–2012
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Centers for Disease Control and Prevention
- Health Effects Laboratory Division
Druid Hills, GA, USA
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2002–2007
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West Virginia University
- • Department of Medicine
- • School of Pharmacy
Morgantown, WV, USA
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