Last data update: Nov 04, 2024. (Total: 48056 publications since 2009)
Records 1-30 (of 46 Records) |
Query Trace: Zeidler-Erdely P[original query] |
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Absence of lung tumor promotion with reduced tumor size in mice after inhalation of copper welding fumes
Zeidler-Erdely PC , Kodali V , Falcone LM , Mercer R , Leonard SS , Stefaniak AB , Grose L , Salmen R , Trainor-DeArmitt T , Battelli LA , McKinney W , Stone S , Meighan TG , Betler E , Friend S , Hobbie KR , Service S , Kashon M , Antonini JM , Erdely A . Carcinogenesis 2024 Welding fumes are a Group 1 (carcinogenic to humans) carcinogen as classified by the International Agency for Research on Cancer. The process of welding creates inhalable fumes rich in iron (Fe) that may also contain known carcinogenic metals such as chromium (Cr) and nickel (Ni). Epidemiological evidence has shown that both mild-steel (Fe-rich) and stainless steel (Fe-rich + Cr + Ni) welding fume exposure increase lung cancer risk, and experimental animal data support these findings. Copper-nickel (CuNi) welding processes have not been investigated in the context of lung cancer. Cu is intriguing, however, given the role of Cu in carcinogenesis and cancer therapeutics. This study examines the potential for a CuNi fume to induce mechanistic key characteristics of carcinogenesis in vitro and to promote lung tumorigenesis, using a two-stage mouse bioassay, in vivo. Male A/J mice, initiated with 3-methylcholanthrene (MCA; 10 µg/g), were exposed to CuNi fumes or air by whole-body inhalation for nine weeks (low-deposition-LD and high deposition-HD) then sacrificed at 30 weeks. In BEAS-2B cells, the CuNi fume induced micronuclei and caused DNA damage as measured by γ-H2AX. The fume exhibited high reactivity and a dose response in cytotoxicity and oxidative stress. In vivo, MCA/CuNi HD and LD significantly decreased lung tumor size and adenomas. MCA/CuNi HD exposure significantly decreased gross-evaluated tumor number. In summary, the CuNi fume in vitro exhibited characteristics of a carcinogen, but in vivo the exposure resulted in smaller tumors, fewer adenomas, less hyperplasia severity, and with the HD exposure, less overall lung lesion/tumors. |
Long noncoding RNA ABHD11-AS1 interacts with SART3 and regulates CD44 RNA alternative splicing to promote lung carcinogenesis
Wang PS , Liu Z , Sweef O , Xie J , Chen J , Zhu H , Zeidler-Erdely PC , Yang C , Wang Z . Environ Int 2024 185 108494 Hexavalent chromium [Cr(VI)] is a common environmental pollutant and chronic exposure to Cr(VI) causes lung cancer in humans, however, the mechanism of Cr(VI) carcinogenesis has not been well understood. Lung cancer is the leading cause of cancer-related death, although the mechanisms of how lung cancer develops and progresses have been poorly understood. While long non-coding RNAs (lncRNAs) are found abnormally expressed in cancer, how dysregulated lncRNAs contribute to carcinogenesis remains largely unknown. The goal of this study is to investigate the mechanism of Cr(VI)-induced lung carcinogenesis focusing on the role of the lncRNA ABHD11 antisense RNA 1 (tail to tail) (ABHD11-AS1). It was found that the lncRNA ABHD11-AS1 expression levels are up-regulated in chronic Cr(VI) exposure-transformed human bronchial epithelial cells, chronically Cr(VI)-exposed mouse lung tissues, and human lung cancer cells as well. Bioinformatics analysis revealed that ABHD11-AS1 levels are up-regulated in lung adenocarcinomas (LUADs) tissues and associated with worse overall survival of LUAD patients but not in lung squamous cell carcinomas. It was further determined that up-regulation of ABHD11-AS1 expression plays an important role in chronic Cr(VI) exposure-induced cell malignant transformation and tumorigenesis, and the stemness of human lung cancer cells. Mechanistically, it was found that ABHD11-AS1 directly binds SART3 (spliceosome associated factor 3, U4/U6 recycling protein). The interaction of ABHD11-AS1 with SART3 promotes USP15 (ubiquitin specific peptidase 15) nuclear localization. Nuclear localized USP15 interacts with pre-mRNA processing factor 19 (PRPF19) to increase CD44 RNA alternative splicing activating β-catenin and enhancing cancer stemness. Together, these findings indicate that lncRNA ABHD11-AS1 interacts with SART3 and regulates CD44 RNA alternative splicing to promote cell malignant transformation and lung carcinogenesis. |
Lung toxicity, deposition, and clearance of thermal spray coating particles with different metal profiles after inhalation in rats
Antonini JM , Kodali V , Meighan TG , McKinney W , Cumpston JL , Leonard HD , Cumpston JB , Friend S , Leonard SS , Andrews R , Zeidler-Erdely PC , Erdely A , Lee EG , Afshari AA . Nanotoxicology 2023 1-18 Thermal spray coating is a process in which molten metal is sprayed onto a surface. Little is known about the health effects associated with these aerosols. Sprague-Dawley rats were exposed to aerosols (25 mg/m(3) × 4 hr/d × 4 d) generated during thermal spray coating using different consumables [i.e. stainless-steel wire (PMET731), Ni-based wire (PMET885), Zn-based wire (PMET540)]. Control animals received air. Bronchoalveolar lavage was performed at 4 and 30 d post-exposure to assess lung toxicity. The particles were chain-like agglomerates and similar in size (310-378 nm). Inhalation of PMET885 aerosol caused a significant increase in lung injury and inflammation at both time points. Inhalation of PMET540 aerosol caused a slight but significant increase in lung toxicity at 4 but not 30 d. Exposure to PMET731 aerosol had no effect on lung toxicity. Overall, the lung responses were in the order: PMET885≫PMET540 >PMT731. Following a shorter exposure (25 mg/m(3) × 4 h/d × 1d), lung burdens of metals from the different aerosols were determined by ICP-AES at 0, 1, 4 and 30 d post-exposure. Zn was cleared from the lungs at the fastest rate with complete clearance by 4 d post-exposure. Ni, Cr, and Mn had similar rates of clearance as nearly half of the deposited metal was cleared by 4 d. A small but significant percentage of each of these metals persisted in the lungs at 30 d. The pulmonary clearance of Fe was difficult to assess because of inherently high levels of Fe in control lungs. |
A review of pulmonary neutrophilia and insights into the key role of neutrophils in particle-induced pathogenesis in the lung from animal studies of lunar dusts and other poorly soluble dust particles
Lam CW , Castranova V , Driscoll K , Warheit D , Ryder V , Zhang Y , Zeidler-Erdely P , Hunter R , Scully R , Wallace W , James J , Crucian B , Nelman M , McCluskey R , Gardner D , Renne R , McClellan R . Crit Rev Toxicol 2023 53 (8) 1-39 The mechanisms of particle-induced pathogenesis in the lung remain poorly understood. Neutrophilic inflammation and oxidative stress in the lung are hallmarks of toxicity. Some investigators have postulated that oxidative stress from particle surface reactive oxygen species (psROS) on the dust produces the toxicopathology in the lungs of dust-exposed animals. This postulate was tested concurrently with the studies to elucidate the toxicity of lunar dust (LD), which is believed to contain psROS due to high-speed micrometeoroid bombardment that fractured and pulverized lunar surface regolith. Results from studies of rats intratracheally instilled (ITI) with three LDs (prepared from an Apollo-14 lunar regolith), which differed 14-fold in levels of psROS, and two toxicity reference dusts (TiO(2) and quartz) indicated that psROS had no significant contribution to the dusts' toxicity in the lung. Reported here are results of further investigations by the LD toxicity study team on the toxicological role of oxidants in alveolar neutrophils that were harvested from rats in the 5-dust ITI study and from rats that were exposed to airborne LD for 4 weeks. The oxidants per neutrophils and all neutrophils increased with dose, exposure time and dust's cytotoxicity. The results suggest that alveolar neutrophils play a critical role in particle-induced injury and toxicity in the lung of dust-exposed animals. Based on these results, we propose an adverse outcome pathway (AOP) for particle-associated lung disease that centers on the crucial role of alveolar neutrophil-derived oxidant species. A critical review of the toxicology literature on particle exposure and lung disease further supports a neutrophil-centric mechanism in the pathogenesis of lung disease and may explain previously reported animal species differences in responses to poorly soluble particles. Key findings from the toxicology literature indicate that (1) after exposures to the same dust at the same amount, rats have more alveolar neutrophils than hamsters; hamsters clear more particles from their lungs, consequently contributing to fewer neutrophils and less severe lung lesions; (2) rats exposed to nano-sized TiO(2) have more neutrophils and more severe lesions in their lungs than rats exposed to the same mass-concentration of micron-sized TiO(2); nano-sized dust has a greater number of particles and a larger total particle-cell contact surface area than the same mass of micron-sized dust, which triggers more alveolar epithelial cells (AECs) to synthesize and release more cytokines that recruit a greater number of neutrophils leading to more severe lesions. Thus, we postulate that, during chronic dust exposure, particle-inflicted AECs persistently release cytokines, which recruit neutrophils and activate them to produce oxidants resulting in a prolonged continuous source of endogenous oxidative stress that leads to lung toxicity. This neutrophil-driven lung pathogenesis explains why dust exposure induces more severe lesions in rats than hamsters; why, on a mass-dose basis, nano-sized dusts are more toxic than the micron-sized dusts; why lung lesions progress with time; and why dose-response curves of particle toxicity exhibit a hockey stick like shape with a threshold. The neutrophil centric AOP for particle-induced lung disease has implications for risk assessment of human exposures to dust particles and environmental particulate matter. |
Examination of the exposome in an animal model: The impact of high fat diet and rat strain on local and systemic immune markers following occupational welding fume exposure.
Roach KA , Kodali V , Shoeb M , Meighan T , Kashon M , Stone S , McKinney W , Erdely A , Zeidler-Erdely PC , Roberts JR , Antonini JM . Toxicol Appl Pharmacol 2023 464 116436 The goal of this study was to investigate the impact of multiple exposomal factors (genetics, lifestyle factors, environmental/occupational exposures) on pulmonary inflammation and corresponding alterations in local/systemic immune parameters. Accordingly, male Sprague-Dawley (SD) and Brown Norway (BN) rats were maintained on either regular (Reg) or high fat (HF) diets for 24wk. Welding fume (WF) exposure (inhalation) occurred between 7 and 12wk. Rats were euthanized at 7, 12, and 24wk to evaluate local and systemic immune markers corresponding to the baseline, exposure, and recovery phases of the study, respectively. At 7wk, HF-fed animals exhibited several immune alterations (blood leukocyte/neutrophil number, lymph node B-cell proportionality)-effects which were more pronounced in SD rats. Indices of lung injury/inflammation were elevated in all WF-exposed animals at 12wk; however, diet appeared to preferentially impact SD rats at this time point, as several inflammatory markers (lymph node cellularity, lung neutrophils) were further elevated in HF over Reg animals. Overall, SD rats exhibited the greatest capacity for recovery by 24wk. In BN rats, resolution of immune alterations was further compromised by HF diet, as many exposure-induced alterations in local/systemic immune markers were still evident in HF/WF animals at 24wk. Collectively, HF diet appeared to have a greater impact on global immune status and exposure-induced lung injury in SD rats, but a more pronounced effect on inflammation resolution in BN rats. These results illustrate the combined impact of genetic, lifestyle, and environmental factors in modulating immunological responsivity and emphasize the importance of the exposome in shaping biological responses. |
In vivo and in vitro toxicity of a stainless-steel aerosol generated during thermal spray coating
Kodali V , Afshari A , Meighan T , McKinney W , Mazumder MHH , Majumder N , Cumpston JL , Leonard HD , Cumpston JB , Friend S , Leonard SS , Erdely A , Zeidler-Erdely PC , Hussain S , Lee EG , Antonini JM . Arch Toxicol 2022 96 (12) 3201-3217 Thermal spray coating is an industrial process in which molten metal is sprayed at high velocity onto a surface as a protective coating. An automated electric arc wire thermal spray coating aerosol generator and inhalation exposure system was developed to simulate an occupational exposure and, using this system, male Sprague-Dawley rats were exposed to stainless steel PMET720 aerosols at 25 mg/m(3) × 4 h/day × 9 day. Lung injury, inflammation, and cytokine alteration were determined. Resolution was assessed by evaluating these parameters at 1, 7, 14 and 28 d after exposure. The aerosols generated were also collected and characterized. Macrophages were exposed in vitro over a wide dose range (0-200 µg/ml) to determine cytotoxicity and to screen for known mechanisms of toxicity. Welding fumes were used as comparative particulate controls. In vivo lung damage, inflammation and alteration in cytokines were observed 1 day post exposure and this response resolved by day 7. Alveolar macrophages retained the particulates even after 28 day post-exposure. In line with the pulmonary toxicity findings, in vitro cytotoxicity and membrane damage in macrophages were observed only at the higher doses. Electron paramagnetic resonance showed in an acellular environment the particulate generated free radicals and a dose-dependent increase in intracellular oxidative stress and NF-kB/AP-1 activity was observed. PMET720 particles were internalized via clathrin and caveolar mediated endocytosis as well as actin-dependent pinocytosis/phagocytosis. The results suggest that compared to stainless steel welding fumes, the PMET 720 aerosols were not as overtly toxic, and the animals recovered from the acute pulmonary injury by 7 days. |
Lung toxicity profile of inhaled copper-nickel welding fume in A/J mice
Zeidler-Erdely PC , Erdely A , Kodali V , Andrews R , Antonini J , Trainor-DeArmitt T , Salmen R , Battelli L , Grose L , Kashon M , Service S , McKinney W , Stone S , Falcone L . Inhal Toxicol 2022 34 1-12 Objective: Stainless steel welding creates fumes rich in carcinogenic metals such as chromium (Cr). Welding consumables devoid of Cr are being produced in an attempt to limit worker exposures to toxic and carcinogenic metals. The study objective was to characterize a copper-nickel (Cu-Ni) fume generated using gas metal arc welding (GMAW) and determine the pulmonary deposition and toxicity of the fume in mice exposed by inhalation. Materials and Methods: Male A/J mice (6-8 weeks of age) were exposed to air or Cu-Ni welding fumes for 2 (low deposition) or 4 (high deposition) hours/day for 10 days. Mice were sacrificed, and bronchoalveolar lavage (BAL), macrophage function, and histopathological analyses were performed at different timepoints post-exposure to evaluate resolution. Results and Discussion: Characterization of the fume indicated that most of the particles were between 0.1 and 1 µm in diameter, with a mass median aerodynamic diameter of 0.43 µm. Metal content of the fume was Cu (∼76%) and Ni (∼12%). Post-exposure, BAL macrophages had a reduced ability to phagocytose E. coli, and lung cytotoxicity was evident and significant (>12%-19% fold change). Loss of body weight was also significant at the early timepoints. Lung inflammation, the predominant finding identified by histopathology, was observed as a subacute response early that progressively resolved by 28 days with only macrophage aggregates remaining late (84 days). Conclusions: Overall, there was high acute lung toxicity with a resolution of the response in mice which suggests that the Cu-Ni fume may not be ideal for reducing toxic and inflammatory lung effects. |
Comparative pulmonary toxicities of lunar dusts and terrestrial dusts (TiO(2) & SiO(2)) in rats and an assessment of the impact of particle-generated oxidants on the dusts' toxicities
Lam CW , Castranova V , Zeidler-Erdely PC , Renne R , Hunter R , McCluskey R , Scully RR , Wallace WT , Zhang Y , Ryder VE , Cooper B , McKay D , McClellan RO , Driscoll KE , Gardner DE , Barger M , Meighan T , James JT . Inhal Toxicol 2022 34 51-67 Humans will set foot on the Moon again soon. The lunar dust (LD) is potentially reactive and could pose an inhalation hazard to lunar explorers. We elucidated LD toxicity and investigated the toxicological impact of particle surface reactivity (SR) using three LDs, quartz, and TiO(2). We first isolated the respirable-size-fraction of an Apollo-14 regolith and ground two coarser samples to produce fine LDs with increased SR. SR measurements of these five respirable-sized dusts, determined by their in-vitro ability to generate hydroxyl radicals (OH), showed that ground LDs>unground LDTiO(2) quartz. Rats were each intratracheally instilled with 0, 1, 2.5, or 7.5mg of a test dust. Toxicity biomarkers and histopathology were assessed up to 13weeks after the bolus instillation. All dusts caused dose-dependent-increases in pulmonary lesions and toxicity biomarkers. The three LDs, which possessed mineral compositions/properties similar to Arizona volcanic ash, were moderately toxic. Despite a 14-fold OH difference among these three LDs, their toxicities were indistinguishable. Quartz produced the lowest OH amount but showed the greatest toxicity. Our results showed no correlation between the toxicity of mineral dusts and their ability to generate free radicals. We also showed that the amounts of oxidants per neutrophil increased with doses, time and the cytotoxicity of the dusts in the lung, which supports our postulation that dust-elicited neutrophilia is the major persistent source of oxidative stress. These results and the discussion of the crucial roles of the short-lived, continuously replenished neutrophils in dust-induced pathogenesis are presented. |
Chronic hexavalent chromium exposure up-regulates the RNA methyltransferase METTL3 expression to promote cell transformation, cancer stem cell-like property and tumorigenesis
Wang Z , Uddin MB , Xie J , Tao H , Zeidler-Erdely PC , Kondo K , Yang C . Toxicol Sci 2022 187 (1) 51-61 Hexavalent chromium [Cr(VI)] is a common environmental carcinogen causing lung cancer in humans. This study investigates the mechanism of Cr(VI) carcinogenesis focusing on the role of the epitranscriptomic dysregulation. The epitranscriptomic effect of Cr(VI) was determined in Cr(VI)-transformed human bronchial epithelial cells, chromate-exposed mouse and human lungs. The epitranscriptomic effect and its role in Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis were determined by microarray analysis, soft agar colony formation, suspension spheroid formation and mouse xenograft tumorigenesis assays. It was found that chronic Cr(VI) exposure causes epitranscriptomic dysregulations as evidenced by the increased levels of total RNA N6-methyladenosine (m6A) modification and the RNA m6A methyltransferase METTL3 in Cr(VI)-transformed cells and chromate exposure-caused mouse and human lung tumors. Knockdown of METTL3 expression in Cr(VI)-transformed cells significantly reduces their m6A levels and transformed phenotypes and tumorigenicity in mice. Moreover, knockdown of METTL3 expression in parental non-transformed cells significantly reduces the capability of chronic Cr(VI) exposure to induce cell transformation and CSC-like property. Together, this study reveals that chronic Cr(VI) exposure is capable of altering cellular epitranscriptome by increasing the m6A RNA modification via upregulating the RNA methyltransferase METTL3 expression, which plays an important role in Cr(VI)-induced cell transformation, CSC-like property and tumorigenesis. |
Oxidant-induced epithelial alarmin pathway mediates lung inflammation and functional decline following ultrafine carbon and ozone inhalation co-exposure
Majumder N , Goldsmith WT , Kodali VK , Velayutham M , Friend SA , Khramtsov VV , Nurkiewicz TR , Erdely A , Zeidler-Erdely PC , Castranova V , Harkema JR , Kelley EE , Hussain S . Redox Biol 2021 46 102092 Environmental inhalation exposures are inherently mixed (gases and particles), yet regulations are still based on single toxicant exposures. While the impacts of individual components of environmental pollution have received substantial attention, the impact of inhalation co-exposures is poorly understood. Here, we mechanistically investigated pulmonary inflammation and lung function decline after inhalation co-exposure and individual exposures to ozone (O(3)) and ultrafine carbon black (CB). Environmentally/occupationally relevant lung deposition levels in mice were achieved after inhalation of stable aerosols with similar aerodynamic and mass median distributions. X-ray photoemission spectroscopy detected increased surface oxygen contents on particles in co-exposure aerosols. Compared with individual exposures, co-exposure aerosols produced greater acellular and cellular oxidants detected by electron paramagnetic resonance (EPR) spectroscopy, and in vivo immune-spin trapping (IST), as well as synergistically increased lavage neutrophils, lavage proteins and inflammation related gene/protein expression. Co-exposure induced a significantly greater respiratory function decline compared to individual exposure. A synthetic catalase-superoxide dismutase mimetic (EUK-134) significantly blunted lung inflammation and respiratory function decline confirming the role of oxidant imbalance. We identified a significant induction of epithelial alarmin (thymic stromal lymphopoietin-TSLP)-dependent interleukin-13 pathway after co-exposure, associated with increased mucin and interferon gene expression. We provided evidence of interactive outcomes after air pollution constituent co-exposure and identified a key mechanistic pathway that can potentially explain epidemiological observation of lung function decline after an acute peak of air pollution. Developing and studying the co-exposure scenario in a standardized and controlled fashion will enable a better mechanistic understanding of how environmental exposures result in adverse outcomes. |
Welding fume inhalation exposure and high-fat diet change lipid homeostasis in rat liver
Boyce GR , Shoeb M , Kodali V , Meighan TG , Roach KA , McKinney W , Stone S , Powell MJ , Roberts JR , Zeidler-Erdely PC , Erdely A , Antonini JM . Toxicol Rep 2020 7 1350-1355 It is estimated that greater than 1 million workers are exposed to welding fume (WF) by inhalation daily. The potentially toxic metals found in WF are known to cause multiple adverse pulmonary and systemic effects, including cardiovascular disease, and these metals have also been shown to translocate to the liver. This occupational exposure combined with a high fat (HF) Western diet, which has been shown to cause hyperlipidemia and non-alcoholic fatty liver disease (NAFLD), has the potential to cause significant mixed exposure metabolic changes in the liver. The goal of this study was to use matrix assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) to analyze the spatial distribution and abundance changes of lipid species in Sprague Dawley rat liver maintained on a HF diet combined with WF inhalation. The results of the MALDI-IMS analysis revealed unique hepatic lipid profiles for each treatment group. The HF diet group had significantly increased abundance of triglycerides and phosphatidylinositol lipids, as well as decreased lysophosphatidic lipids and cardiolipin. Ceramide-1-phosphate was found at higher abundance in the regular (REG) diet WF-exposed group which has been shown to regulate the eicosanoid pathway involved in pro-inflammatory response. The results of this study showed that the combined effects of WF inhalation and a HF diet significantly altered the hepatic lipidome. Additionally, pulmonary exposure to WF alone increased lipid markers of inflammation. |
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. |
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. |
Association of occupational exposures with ex vivo functional immune response in workers handling carbon nanotubes and nanofibers
Schubauer-Berigan MK , Dahm MM , Toennis CA , Sammons DL , Eye T , Kodali V , Zeidler-Erdely PC , Erdely A . Nanotoxicology 2020 14 (3) 1-16 The objective of this study was to evaluate the association between carbon nanotube and nanofiber (CNT/F) exposure and ex vivo responses of whole blood challenged with secondary stimulants, adjusting for potential confounders, in a cross-sectional study of 102 workers. Multi-day exposure was measured by CNT/F structure count (SC) and elemental carbon (EC) air concentrations. Demographic, lifestyle and other occupational covariate data were obtained via questionnaire. Whole blood collected from each participant was incubated for 18 hours with and without two microbial stimulants (lipopolysaccharide/LPS and staphylococcal enterotoxin type B/SEB) using TruCulture technology to evaluate immune cell activity. Following incubation, supernatants were preserved and analyzed for protein concentrations. The stimulant:null response ratio for each individual protein was analyzed using multiple linear regression, followed by principal component (PC) analysis to determine whether patterns of protein response were related to CNT/F exposure. Adjusting for confounders, CNT/F metrics (most strongly, the SC-based) were significantly (p < 0.05) inversely associated with stimulant:null ratios of several individual biomarkers: GM-CSF, IFN-gamma, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-17, and IL-23. CNT/F metrics were significantly inversely associated with PC1 (a weighted mean of most biomarkers, explaining 25% of the variance in the protein ratios) and PC2 (a biomarker contrast, explaining 14%). Among other occupational exposures, only solvent exposure was significant (inversely related to PC2). CNT/F exposure metrics were uniquely related to stimulant responses in challenged whole blood, illustrating reduced responsiveness to a secondary stimulus. This approach, if replicated in other exposed populations, may present a relatively sensitive method to evaluate human response to CNT/F or other occupational exposures. |
Effect of a high fat diet and occupational exposure in different rat strains on lung and systemic responses: examination of the exposome in an animal model
Antonini JM , Kodali V , Shoeb M , Kashon M , Roach KA , Boyce G , Meighan T , Stone S , McKinney W , Boots T , Roberts JR , Zeidler-Erdely PC , Erdely A . Toxicol Sci 2019 174 (1) 100-111 The exposome is the measure of all exposures of an individual in a lifetime and how those exposures relate to health. The goal was to examine an experimental model integrating multiple aspects of the exposome by collecting biological samples during critical life stages of an exposed animal that are applicable to worker populations. Genetic contributions were assessed using strains of male rats with different genetic backgrounds [Fischer-344, Sprague-Dawley, Brown-Norway] maintained on a regular (REG) or high fat (HF) diet for 24 wk. At wk 7 during diet maintenance, groups of rats from each strain were exposed to stainless steel welding fume (WF; 20 mg/m3 x 3 hr/d x 4 d/wk x 5 wk) or air until wk 12, at which time some animals were euthanized. A separate set of rats from each strain were allowed to recover from WF exposure until the end of the 24 wk period. Bronchoalveolar lavage fluid and serum were collected at 7, 12, and 24 wk to assess general health indices. Depending on animal strain, WF exposure and HF diet together worsened kidney toxicity as well as altered different serum enzymes and proteins. Diet had minimal interaction with WF exposure for pulmonary toxicity endpoints. Experimental factors of diet, exposure, and strain were all important, depending on the health outcome measured. Exposure had the most significant influence related to pulmonary responses. Strain was the most significant contributor regarding the other health indices examined, indicating that genetic differences possibly drive the exposome effect in each strain. |
Nanoparticle exposure driven circulating bioactive peptidome causes systemic inflammation and vascular dysfunction
Mostovenko E , Young T , Muldoon PP , Bishop L , Canal CG , Vucetic A , Zeidler-Erdely PC , Erdely A , Campen MJ , Ottens AK . Part Fibre Toxicol 2019 16 (1) 20 The mechanisms driving systemic effects consequent pulmonary nanoparticle exposure remain unclear. Recent work has established the existence of an indirect process by which factors released from the lung into the circulation promote systemic inflammation and cellular dysfunction, particularly on the vasculature. However, the composition of circulating contributing factors and how they are produced remains unknown. Evidence suggests matrix protease involvement; thus, here we used a well-characterized multi-walled carbon nanotube (MWCNT) oropharyngeal aspiration model with known vascular effects to assess the distinct contribution of nanoparticle-induced peptide fragments in driving systemic pathobiology. |
Influence of welding fume metal composition on lung toxicity and tumor formation in experimental animal models
Zeidler-Erdely PC , Falcone LM , Antonini JM . J Occup Environ Hyg 2019 16 (6) 1-6 Millions of workers in the US and worldwide are exposed to complex, metal-rich welding fumes. Although welding is a crucial industrial process, the generated fumes are known to cause acute and chronic health effects when inhaled. The International Agency for Research on Cancer (IARC) classified welding fumes as carcinogenic to humans (Group 1) in 2017, based on sufficient epidemiological evidence and limited evidence in animals, an upgrade from the former Group 2B (possibly carcinogenic to humans) classification. There is human evidence that both iron-abundant mild steel as well as chromium- and nickel-containing stainless steel welding fumes contribute to an increased risk of lung cancer. Recent animal studies show that welding fumes may act as lung tumor promoters, regardless of the presence or absence of potentially carcinogenic metals, such as chromium and nickel. The goal of this manuscript was to examine the pulmonary responses associated with welding fumes by reviewing a series of recent experimental animal studies that assessed the influence of welding fume metal composition (e.g., stainless steel versus mild steel welding fume) on markers of lung toxicity and tumor development. Additional in vivo laboratory studies are needed to further explore the association between welding and lung cancer and to help advance our understanding of a potential mechanistic link. |
Effect of Age, High-Fat Diet, and Rat Strain on Serum Biomarkers and Telomere Length and Global DNA Methylation in Peripheral Blood Mononuclear Cells.
Antonini JM , Kodali V , Meighan TG , Roach KA , Roberts JR , Salmen R , Boyce GR , Zeidler-Erdely PC , Kashon M , Erdely A , Shoeb M . Sci Rep 2019 9 (1) 1996 The objective of the current study was to determine if age, diet, and genetic disposition (animal strain) in an animal model had early effects on specific molecular markers in circulating peripheral blood mononuclear cells (PBMCs). Three strains [Sprague-Dawley (SD), Fischer 344 (F344), and Brown-Norway (BN)] of male rats were maintained on a high-fat (HF) or regular diet. Blood was collected at 4, 12, and 24 wk to assess chemistry and to recover PBMCs. Triglycerides and body weight gain increased at all time points in the HF diet group for each strain. Telomere length in PBMCs decreased in the HF diet group compared to the regular diet group up to 24 wk in all strains. Telomere length decreased in PBMCs at 24 wk compared to baseline in all strains, indicating an age-related effect. These findings highlight that diet and age cause changes in PBMCs recovered from different strains of rats. The next tier of studies will examine the contribution of an occupational exposure (e.g., welding fume inhalation) in combination with diet, age, and strain, to assess changes in the molecular responses of isolated PBMCs. In addition, studies involving lifestyle exposure (e.g., tobacco smoke) are in the planning stages and will assess the long-term effects of exposure in our animal model. |
Pulmonary toxicity and lung tumorigenic potential of surrogate metal oxides in gas metal arc welding-stainless steel fume: Iron as a primary mediator versus chromium and nickel
Falcone LM , Erdely A , Salmen R , Keane M , Battelli L , Kodali V , Bowers L , Stefaniak AB , Kashon ML , Antonini JM , Zeidler-Erdely PC . PLoS One 2018 13 (12) e0209413 In 2017, the International Agency for Research on Cancer classified welding fumes as "carcinogenic to humans" (Group 1). Both mild steel (MS) welding, where fumes lack carcinogenic chromium and nickel, and stainless steel (SS) increase lung cancer risk in welders; therefore, further research to better understand the toxicity of the individual metals is needed. The objectives were to (1) compare the pulmonary toxicity of chromium (as Cr(III) oxide [Cr2O3] and Cr (VI) calcium chromate [CaCrO4]), nickel [II] oxide (NiO), iron [III] oxide (Fe2O3), and gas metal arc welding-SS (GMAW-SS) fume; and (2) determine if these metal oxides can promote lung tumors. Lung tumor susceptible A/J mice (male, 4-5 weeks old) were exposed by oropharyngeal aspiration to vehicle, GMAW-SS fume (1.7 mg), or a low or high dose of surrogate metal oxides based on the respective weight percent of each metal in the fume: Cr2O3 + CaCrO4 (366 + 5 mug and 731 + 11 mug), NiO (141 and 281 mug), or Fe2O3 (1 and 2 mg). Bronchoalveolar lavage, histopathology, and lung/liver qPCR were done at 1, 7, 28, and 84 days post-aspiration. In a two-stage lung carcinogenesis model, mice were initiated with 3-methylcholanthrene (10 mug/g; intraperitoneal; 1x) or corn oil then exposed to metal oxides or vehicle (1 x/week for 5 weeks) by oropharyngeal aspiration. Lung tumors were counted at 30 weeks post-initiation. Results indicate the inflammatory potential of the metal oxides was Fe2O3 > Cr2O3 + CaCrO4 > NiO. Overall, the pneumotoxic effects were negligible for NiO, acute but not persistent for Cr2O3 + CaCrO4, and persistent for the Fe2O3 exposures. Fe2O3, but not Cr2O3 + CaCrO4 or NiO significantly promoted lung tumors. These results provide experimental evidence that Fe2O3 is an important mediator of welding fume toxicity and support epidemiological findings and the IARC classification. |
Skin cancer and welding
Falcone LM , Zeidler-Erdely PC . Clin Exp Dermatol 2018 44 (2) 130-134 Many workers in several different occupations can be exposed to ultraviolet radiation (UVR), which may increase their risk of developing skin cancer. Welding, an occupation employing an estimated 11 million people worldwide, is one such occupation. Welders are known to be exposed to the full spectrum of UVR from the welding arc and often experience burns and localized cutaneous erythema. In 2017, UVR from welding was classified as carcinogenic to humans based on sufficient evidence of ocular melanoma in humans. It has been hypothesized that exposure to UVR from the welding arc also may increase the risk of skin cancer among workers in this occupation. This review summarizes the current literature on skin cancer risk in welders. |
Inhalation of iron-abundant gas metal arc welding-mild steel fume promotes lung tumors in mice
Falcone LM , Erdely A , Kodali V , Salmen R , Battelli LA , Dodd T , McKinney W , Stone S , Donlin M , Leonard HD , Cumpston JL , Cumpston JB , Andrews RN , Kashon ML , Antonini JM , Zeidler-Erdely PC . Toxicology 2018 409 24-32 Welding fumes were reclassified as a Group 1 carcinogen by the International Agency for Research on Cancer in 2017. Gas metal arc welding (GMAW) is a process widely used in industry. Fume generated from GMAW-mild steel (MS) is abundant in iron with some manganese, while GMAW-stainless steel (SS) fume also contains significant amounts of chromium and nickel, known carcinogenic metals. It has been shown that exposure to GMAW-SS fume in A/J mice promotes lung tumors. The objective was to determine if GMAW-MS fume, which lacks known carcinogenic metals, also promotes lung tumors in mice. Male A/J mice received a single intraperitoneal injection of corn oil or the initiator 3-methylcholanthrene (MCA; 10 mug/g) and, one week later, were exposed by whole-body inhalation to GMAW-MS aerosols for 4 hours/day x 4 days/week x 8 weeks at a mean concentration of 34.5 mg/m(3). Lung nodules were enumerated by gross examination at 30 weeks post-initiation. GMAW-MS fume significantly increased lung tumor multiplicity in mice initiated with MCA (21.86 +/- 1.50) compared to MCA/air-exposed mice (8.34 +/- 0.59). Histopathological analysis confirmed these findings and also revealed an absence of inflammation. Bronchoalveolar lavage analysis also indicated a lack of lung inflammation and toxicity after short-term inhalation exposure to GMAW-MS fume. In conclusion, this study demonstrates that inhalation of GMAW-MS fume promotes lung tumors in vivo and aligns with epidemiologic evidence that shows MS welders, despite less exposure to carcinogenic metals, are at an increased risk for lung cancer. |
Sparse supervised classification methods predict and characterize nanomaterial exposures: Independent markers of MWCNT exposures
Yanamala N , Orandle MS , Kodali VK , Bishop L , Zeidler-Erdely PC , Roberts JR , Castranova V , Erdely A . Toxicol Pathol 2017 46 (1) 192623317730575 Recent experimental evidence indicates significant pulmonary toxicity of multiwalled carbon nanotubes (MWCNTs), such as inflammation, interstitial fibrosis, granuloma formation, and carcinogenicity. Although numerous studies explored the adverse potential of various CNTs, their comparability is often limited. This is due to differences in administered dose, physicochemical characteristics, exposure methods, and end points monitored. Here, we addressed the problem through sparse classification method, a supervised machine learning approach that can reduce the noise contained in redundant variables for discriminating among MWCNT-exposed and MWCNT-unexposed groups. A panel of proteins measured from bronchoalveolar lavage fluid (BAL) samples was used to predict exposure to various MWCNT and determine markers that are attributable to MWCNT exposure and toxicity in mice. Using sparse support vector machine-based classification technique, we identified a small subset of proteins clearly distinguishing each exposure. Macrophage-derived chemokine (MDC/CCL22), in particular, was associated with various MWCNT exposures and was independent of exposure method employed, that is, oropharyngeal aspiration versus inhalation exposure. Sustained expression of some of the selected protein markers identified also suggests their potential role in MWCNT-induced toxicity and proposes hypotheses for future mechanistic studies. Such approaches can be used more broadly for nanomaterial risk profiling studies to evaluate decisions related to dose/time-response relationships that could delineate experimental variables from exposure markers. |
In Vivo Toxicity Assessment of Occupational Components of the Carbon Nanotube Life Cycle To Provide Context to Potential Health Effects
Bishop L , Cena L , Orandle M , Yanamala N , Dahm MM , Birch ME , Evans DE , Kodali VK , Eye T , Battelli L , Zeidler-Erdely PC , Casuccio G , Bunker K , Lupoi JS , Lersch TL , Stefaniak AB , Sager T , Afshari A , Schwegler-Berry D , Friend S , Kang J , Siegrist KJ , Mitchell CA , Lowry DT , Kashon ML , Mercer RR , Geraci CL , Schubauer-Berigan MK , Sargent LM , Erdely A . ACS Nano 2017 11 (9) 8849-8863 Pulmonary toxicity studies on carbon nanotubes focus primarily on as-produced materials and rarely are guided by a life cycle perspective or integration with exposure assessment. Understanding toxicity beyond the as-produced, or pure native material, is critical, due to modifications needed to overcome barriers to commercialization of applications. In the first series of studies, the toxicity of as-produced carbon nanotubes and their polymer-coated counterparts was evaluated in reference to exposure assessment, material characterization, and stability of the polymer coating in biological fluids. The second series of studies examined the toxicity of aerosols generated from sanding polymer-coated carbon-nanotube-embedded or neat composites. Postproduction modification by polymer coating did not enhance pulmonary injury, inflammation, and pathology or in vitro genotoxicity of as-produced carbon nanotubes, and for a particular coating, toxicity was significantly attenuated. The aerosols generated from sanding composites embedded with polymer-coated carbon nanotubes contained no evidence of free nanotubes. The percent weight incorporation of polymer-coated carbon nanotubes, 0.15% or 3% by mass, and composite matrix utilized altered the particle size distribution and, in certain circumstances, influenced acute in vivo toxicity. Our study provides perspective that, while the number of workers and consumers increases along the life cycle, toxicity and/or potential for exposure to the as-produced material may greatly diminish. |
Evaluation of the molecular mechanisms associated with cytotoxicity and inflammation after pulmonary exposure to different metal-rich welding particles
Shoeb M , Kodali V , Farris B , Bishop LM , Meighan T , Salmen R , Eye T , Roberts JR , Zeidler-Erdely P , Erdely A , Antonini JM . Nanotoxicology 2017 11 (6) 1-34 Welding generates a complex aerosol of incidental nanoparticles and cytotoxic metals, such as chromium (Cr), manganese (Mn), nickel (Ni), and iron (Fe). The goal was to use both in vivo and in vitro methodologies to determine the mechanisms by which different welding fumes may damage the lungs. Sprague-Dawley rats were treated by intratracheal instillation (ITI) with 2.0 mg of gas metal arc-mild steel (GMA-MS) or manual metal arc-stainless steel (MMA-SS) fumes or saline (vehicle control). At 1, 3, and 10 days, bronchoalveolar lavage (BAL) was performed to measure lung toxicity. To assess molecular mechanisms of cytotoxicity, RAW264.7 cells were exposed to both welding fumes for 24 hours (0-100 mug/ml). Fume composition was different: MMA-SS (41% Fe, 29% Cr, 17% Mn, 3% Ni) versus GMA-MS (85% Fe, 14% Mn). BAL indicators of lung injury and inflammation were increased by MMA-SS at all time points and by GMA-MS at 3 and 10 days after exposure. RAW264.7 cells exposed to MMA-SS had elevated generation of reactive oxygen species (ROS), protein-HNE (P-HNE) adduct formation, activation of ERK1/2, and expression of cyclooxygenase-2 (COX-2) compared to GMA-MS and control. Increased generation of ROS due to MMA-SS exposure was confirmed by increased expression of Nrf2 and heme oxygenase-1 (HO-1). Results of in vitro studies provide evidence that stainless steel welding fume mediate inflammatory responses via activation of ROS/P-HNE/ERK1/2/Nrf2 signaling pathways. These findings were corroborated by elevated expression of COX-2, Nrf2, and HO-1 in homogenized lung tissue collected 1 day after in vivo exposure. |
Aerosol characterization and pulmonary responses in rats after short-term inhalation of fumes generated during resistance spot welding of galvanized steel
Antonini JM , Afshari A , Meighan TG , McKinney W , Jackson M , Schwegler-Berry D , Burns DA , LeBouf RF , Chen BT , Shoeb M , Zeidler-Erdely PC . Toxicol Rep 2017 4 123-133 Resistance spot welding is a common process to join metals in the automotive industry. Adhesives are often used as sealers to seams of metals that are joined. Anti-spatter compounds sometimes are sprayed onto metals to be welded to improve the weldability. Spot welding produces complex aerosols composed of metal and volatile compounds (VOCs) which can cause lung disease in workers. Male Sprague-Dawley rats (n = 12/treatment group) were exposed by inhalation to 25 mg/m3 of aerosol for 4 h/day × 8 days during spot welding of galvanized zinc (Zn)-coated steel in the presence or absence of a glue or anti-spatter spray. Controls were exposed to filtered air. Particle size distribution and chemical composition of the generated aerosol were determined. At 1 and 7 days after exposure, bronchoalveolar lavage (BAL) was performed to assess lung toxicity. The generated particles mostly were in the submicron size range with a significant number of nanometer-sized particles formed. The primary metals present in the fumes were Fe (72.5%) and Zn (26.3%). The addition of the anti-spatter spray and glue did affect particle size distribution when spot welding galvanized steel, whereas they had no effect on metal composition. Multiple VOCs (e.g., methyl methacrylate, acetaldehyde, ethanol, acetone, benzene, xylene) were identified when spot welding using either the glue or the anti-spatter spray that were not present when welding alone. Markers of lung injury (BAL lactate dehydrogenase) and inflammation (total BAL cells/neutrophils and cytokines/chemokines) were significantly elevated compared to controls 1 day after exposure to the spot welding fumes. The elevated pulmonary response was transient as lung toxicity mostly returned to control values by 7 days. The VOCs or the concentrations that they were generated during the animal exposures had no measurable effect on the pulmonary responses. Inhalation of galvanized spot welding fumes caused acute lung toxicity most likely due to the short-term exposure of particles that contain Zn. |
Oxidative stress, DNA methylation, and telomere length changes in peripheral blood mononuclear cells after pulmonary exposure to metal-rich welding nanoparticles
Shoeb M , Kodali VK , Farris BY , Bishop LM , Meighan TG , Salmen R , Eye T , Friend S , Schwegler-Berry D , Roberts JR , Zeidler-Erdely PC , Erdely A , Antonini JM . NanoImpact 2017 5 61-69 Welding fume is a complex mixture of different potentially cytotoxic and genotoxic metals, such as chromium (Cr), manganese (Mn), nickel (Ni), and iron (Fe). Documented health effects have been observed in workers exposed to welding fume. The objective of the study was to use an animal model to identify potential biomarkers of epigenetic changes (e.g., changes in telomere length, DNA methylation) in isolated peripheral blood mononuclear cells (PBMCs) after exposure to different welding fumes. Male Sprague-Dawley rats were exposed by intratracheal instillation (ITI) of 2.0 mg/rat of gas metal arc-mild steel (GMA-MS) or manual metal arc-stainless steel (MMA-SS) welding fume. Vehicle controls received sterile saline by ITI. At 4 h, 14 h, 1 d, 3 d, 10 d, and 30 d, bronchoalveolar lavage (BAL) was performed to assess lung inflammation. Whole blood was collected, and PBMCs were isolated. Dihydroethidium (DHE) fluorescence and 4-hydroxylnonenal protein adduct (P-HNE) formation were measured in PBMCs to assess reactive oxygen species production. DNA alterations in PBMCs were determined by evaluating changes in DNA methylation and telomere length. Metal composition of the two fumes was different: MMA-SS (41% Fe, 29% Cr, 17% Mn, 3% Ni) versus GMA-MS (85% Fe, 14% Mn). The more soluble and chemically complex MMA-SS sample induced a more persistent and greater inflammatory response compared to the other groups. Also, oxidative stress markers increased at 24 h in the PBMCs recovered from the MMA-SS group compared to other group. No significant differences were observed when comparing DNA methylation between the welding fume and control groups at any of the time points, whereas the MMA-SS sample significantly increased telomere length at 1 and 30 d after a single exposure compared to the other groups. These findings suggest that genotoxic (e.g., Cr, Ni) and soluble (e.g, Cr, Mn) metals in MMA-SS fume, that are different from the GMA-MS fume, may enhance lung toxicity, as well as induce markers of oxidative stress and increase telomere length in PBMCs. Importantly, the measurement of telomere length in cells isolated from peripheral blood may serve as a potential biomarker of response in the assessment of toxicity associated with welding fumes. |
Inhalation of gas metal arc-stainless steel welding fume promotes lung tumorigenesis in A/J mice
Falcone LM , Erdely A , Meighan TG , Battelli LA , Salmen R , McKinney W , Stone S , Cumpston A , Cumpston J , Andrews RN , Kashon M , Antonini JM , Zeidler-Erdely PC . Arch Toxicol 2017 91 (8) 2953-2962 Epidemiologic studies suggest an increased risk of lung cancer with exposure to welding fumes, but controlled animal studies are needed to support this association. Oropharyngeal aspiration of collected "aged" gas metal arc-stainless steel (GMA-SS) welding fume has been shown by our laboratory to promote lung tumor formation in vivo using a two-stage initiation-promotion model. Our objective in this study was to determine whether inhalation of freshly generated GMA-SS welding fume also acts as a lung tumor promoter in lung tumor-susceptible mice. Male A/J mice received intraperitoneal (IP) injections of corn oil or the chemical initiator 3-methylcholanthrene (MCA; 10 microg/g) and 1 week later were exposed by whole-body inhalation to air or GMA-SS welding aerosols for 4 h/d x 4 d/w x 9 w at a target concentration of 40 mg/m3. Lung nodules were enumerated at 30 weeks post-initiation. GMA-SS fume significantly promoted lung tumor multiplicity in A/J mice initiated with MCA (16.11 +/- 1.18) compared to MCA/air-exposed mice (7.93 +/- 0.82). Histopathological analysis found that the increased number of lung nodules in the MCA/GMA-SS group were hyperplasias and adenomas, which was consistent with developing lung tumorigenesis. Metal deposition analysis in the lung revealed a lower deposited dose, approximately fivefold compared to our previous aspiration study, still elicited a significant lung tumorigenic response. In conclusion, this study demonstrates that inhaling GMA-SS welding fume promotes lung tumorigenesis in vivo which is consistent with the epidemiologic studies that show welders may be at an increased risk for lung cancer. |
Comparison of cell counting methods in rodent pulmonary toxicity studies: automated and manual protocols and considerations for experimental design
Zeidler-Erdely PC , Antonini JM , Meighan TG , Young SH , Eye TJ , Hammer MA , Erdely A . Inhal Toxicol 2016 28 (9) 1-11 Pulmonary toxicity studies often use bronchoalveolar lavage (BAL) to investigate potential adverse lung responses to a particulate exposure. The BAL cellular fraction is counted, using automated (i.e. Coulter Counter(R)), flow cytometry or manual (i.e. hemocytometer) methods, to determine inflammatory cell influx. The goal of the study was to compare the different counting methods to determine which is optimal for examining BAL cell influx after exposure by inhalation or intratracheal instillation (ITI) to different particles with varying inherent pulmonary toxicities in both rat and mouse models. General findings indicate that total BAL cell counts using the automated and manual methods tended to agree after inhalation or ITI exposure to particle samples that are relatively nontoxic or at later time points after exposure to a pneumotoxic particle when the response resolves. However, when the initial lung inflammation and cytotoxicity was high after exposure to a pneumotoxic particle, significant differences were observed when comparing cell counts from the automated, flow cytometry and manual methods. When using total BAL cell count for differential calculations from the automated method, depending on the cell diameter size range cutoff, the data suggest that the number of lung polymorphonuclear leukocytes (PMN) varies. Importantly, the automated counts, regardless of the size cutoff, still indicated a greater number of total lung PMN when compared with the manual method, which agreed more closely with flow cytometry. The results suggest that either the manual method or flow cytometry would be better suited for BAL studies where cytotoxicity is an unknown variable. |
MMP-9-dependent serum-borne bioactivity caused by multi-walled carbon nanotube exposure induces vascular dysfunction via the CD36 scavenger receptor
Aragon M , Erdely A , Bishop L , Salmen R , Weaver J , Liu J , Hall P , Eye T , Kodali V , Zeidler-Erdely P , Stafflinger JE , Ottens AK , Campen MJ . Toxicol Sci 2016 150 (2) 488-98 Inhalation of multi-walled carbon nanotubes (MWCNT) causes systemic effects including vascular inflammation, endothelial dysfunction, and acute phase protein expression. MWCNTs translocate only minimally beyond the lungs, thus cardiovascular effects thereof may be caused by generation of secondary biomolecular factors from MWCNT-pulmonary interactions that spill over into the systemic circulation. Therefore, we hypothesized that induced matrix metalloproteinase-9 (MMP-9) is a generator of factors that, in turn, drive vascular effects through ligand-receptor interactions with the multiligand pattern recognition receptor, CD36. To test this, wildtype (WT; C57BL/6) and MMP-9-/- mice were exposed to varying doses (10 or 40 microg) of MWCNTs via oropharyngeal aspiration and serum was collected at 4 and 24 h post-exposure. Endothelial cells treated with serum from MWCNT-exposed WT mice exhibited significantly reduced nitric oxide (NO) generation, as measured by electron paramagnetic resonance, an effect that was independent of NO scavenging. Serum from MWCNT-exposed WT mice inhibited acetylcholine-mediated relaxation of aortic rings at both time points. Absence of CD36 on the aortic rings (obtained from CD36-deficient mice) abolished the serum-induced impairment of vasorelaxation. MWCNT exposure induced MMP-9 protein levels in both bronchoalveolar lavage and whole lung lysates. Serum from MMP-9-/- mice exposed to MWCNT did not diminish the magnitude of vasorelaxation in naive WT aortic rings, although a modest right shift of the acetylcholine dose-response curve was observed in both MWCNT dose groups relative to controls. In conclusion, pulmonary exposure to MWCNT leads to elevated MMP-9 levels and MMP-9-dependent generation of circulating bioactive factors that promote endothelial dysfunction and decreased NO bioavailability via interaction with vascular CD36. |
Cardiac and mitochondrial dysfunction following acute pulmonary exposure to mountaintop removal mining particulate matter
Nichols CE , Shepherd DL , Knuckles TL , Thapa D , Stricker JC , Stapleton PA , Minarchick VC , Erdely A , Zeidler-Erdely PC , Alway SE , Nurkiewicz TR , Hollander JM . Am J Physiol Heart Circ Physiol 2015 309 (12) ajpheart 00353 2015 Throughout the United States, air pollution correlates with adverse health outcomes and cardiovascular disease incidence is commonly increased following environmental exposure. In areas surrounding active mountaintop removal mines (MTM) a further increase in cardiovascular morbidity is observed and may be attributed in part to particulate matter (PM) released from the mine. The mitochondrion has been shown to be central in the etiology of many cardiovascular diseases, yet its role in PM related cardiovascular effects are not realized. In this study we sought to elucidate the cardiac processes that are disrupted following exposure to mountaintop removal mining particulate matter (PMMTM). To address this question we exposed male Sprague-Dawley rats to PMMTM, collected within one mile of an active MTM site, using intratracheal instillation. Twenty-four hours following exposure we evaluated cardiac function, apoptotic indices and mitochondrial function. PMMTM exposure, elicited a significant decrease in ejection fraction and fractional shortening compared to controls. Investigation into the cellular impacts of PMMTM exposure identified a significant increase in mitochondrial-induced apoptosis as reflected by an increase in TUNEL positive nuclei and increased caspase-3 and -9 activities. Finally, a significant increase in mitochondrial transition pore opening leading to decreased mitochondrial function was identified following exposure. In conclusion, our data suggest that pulmonary exposure to PMMTM increases cardiac mitochondrial-associated apoptosis and decreases mitochondrial function concomitant with decreased cardiac function. These results suggest that increased cardiovascular disease incidence in populations surrounding MTM mines may be associated with increased cardiac cell apoptosis and decreased mitochondrial function. |
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