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Oxidant-induced epithelial alarmin pathway mediates lung inflammation and functional decline following ultrafine carbon and ozone inhalation co-exposure.

ABSTRACT: 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 (O₃) 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.

SUBMITTER: Majumder N

PROVIDER: S-EPMC8385153 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAir pollution is a complex mixture of particles and gases, yet current regulations are based on single toxicant levels failing to consider potential interactive outcomes of co-exposures. We examined transcriptomic changes after inhalation co-exposure to a particulate and a gaseous component of air pollution and hypothesized that co-exposure would induce significantly greater impairments to mitochondrial bioenergetics. A whole-body inhalation exposure to ultrafine carbon black (CB), and ozone (O3) was performed, and the impact of single and multiple exposures was studied at relevant deposition levels. C57BL/6 mice were exposed to CB (10 mg/m3) and/or O3 (2 ppm) for 3 h (either a single exposure or four independent exposures). RNA was isolated from lungs and mRNA sequencing performed using the Illumina HiSeq. Lung pathology was evaluated by histology and immunohistochemistry. Electron transport chain (ETC) activities, electron flow, hydrogen peroxide production, and ATP content were assessed.ResultsCompared to individual exposure groups, co-exposure induced significantly greater neutrophils and protein levels in broncho-alveolar lavage fluid as well as a significant increase in mRNA expression of oxidative stress and inflammation related genes. Similarly, a significant increase in hydrogen peroxide production was observed after co-exposure. After single and four exposures, co-exposure revealed a greater number of differentially expressed genes (2251 and 4072, respectively). Of these genes, 1188 (single exposure) and 2061 (four exposures) were uniquely differentially expressed, with 35 mitochondrial ETC mRNA transcripts significantly impacted after four exposures. Both O3 and co-exposure treatment significantly reduced ETC maximal activity for complexes I (- 39.3% and - 36.2%, respectively) and IV (- 55.1% and - 57.1%, respectively). Only co-exposure reduced ATP Synthase activity (- 35.7%) and total ATP content (30%). Further, the ability for ATP Synthase to function is limited by reduced electron flow (- 25%) and translation of subunits, such as ATP5F1, following co-exposure.ConclusionsCB and O3 co-exposure cause unique transcriptomic changes in the lungs that are characterized by functional deficits to mitochondrial bioenergetics. Alterations to ATP Synthase function and mitochondrial electron flow underly a pathological adaptation to lung injury induced by co-exposure.

Project description:BACKGROUND:Recent epidemiological studies indicate early-life exposure to air pollution is associated with adverse neurodevelopmental outcomes. Previous studies investigating neonatal exposure to ambient fine and ultrafine particles have shown sex specific inflammation-linked pathological changes and protracted learning deficits. A potential contributor to the adverse phenotypes from developmental exposure to particulate matter observed in previous studies may be elemental carbon, a well-known contributor to pollution particulate. The present study is an evaluation of pathological and protracted behavioral alterations in adulthood following subacute neonatal exposure to ultrafine elemental carbon. C57BL/6J mice were exposed to ultrafine elemental carbon at 50??g/m3 from postnatal days 4-7 and 10-13 for 4?h/day. Behavioral outcomes measured were locomotor activity, novel object recognition (short-term memory), elevated plus maze (anxiety-like behavior), fixed interval (FI) schedule of food reward (learning, timing) and differential reinforcement of low rate (DRL) schedule of food reward (impulsivity, inability to inhibit responding). Neuropathology was assessed by measures of inflammation (glial fibrillary-acidic protein), myelin basic protein expression in the corpus callosum, and lateral ventricle area. RESULTS:Twenty-four hours following the final exposure day, no significant differences in anogenital distance, body weight or central nervous system pathological markers were observed in offspring of either sex. Nor were significant changes observed in novel object recognition, elevated plus maze performance, FI, or DRL schedule-controlled behavior in either females or males. CONCLUSION:The limited effect of neonatal exposure to ultrafine elemental carbon suggests this component of air pollution is not a substantial contributor to the behavioral alterations and neuropathology previously observed in response to ambient pollution particulate exposures. Rather, other more reactive constituent species, organic and/or inorganic, gas-phase components, or combinations of constituents may be involved. Defining these neurotoxic components is critical to the formulation of better animal models, more focused mechanistic assessments, and potential regulatory policies for air pollution.

Project description:BACKGROUND: Studies have shown a relationship between air pollution and increased risk of cardiovascular morbidity and mortality. Due to the complexity of ambient air pollution composition, recent studies have examined the effects of co-exposure, particularly particulate matter (PM) and gas, to determine whether pollutant interactions alter (e.g. synergistically, antagonistically) the health response. This study examines the independent effects of fine (FCAPs) and ultrafine (UFCAPs) concentrated ambient particles on cardiac function, and determine the impact of ozone (O?) co-exposure on the response. We hypothesized that UFCAPs would cause greater decrement in mechanical function and electrical dysfunction than FCAPs, and that O? co-exposure would enhance the effects of both particle-types. METHODS: Conscious/unrestrained radiotelemetered mice were exposed once whole-body to either 190 ?g/m³ FCAPs or 140 ?g/m³ UFCAPs with/without 0.3 ppm O?; separate groups were exposed to either filtered air (FA) or O? alone. Heart rate (HR) and electrocardiogram (ECG) were recorded continuously before, during and after exposure, and cardiac mechanical function was assessed using a Langendorff perfusion preparation 24 hrs post-exposure. RESULTS: FCAPs alone caused a significant decrease in baseline left ventricular developed pressure (LVDP) and contractility, whereas UFCAPs did not; neither FCAPs nor UFCAPs alone caused any ECG changes. O? co-exposure with FCAPs caused a significant decrease in heart rate variability when compared to FA but also blocked the decrement in cardiac function. On the other hand, O? co-exposure with UFCAPs significantly increased QRS-interval, QTc and non-conducted P-wave arrhythmias, and decreased LVDP, rate of contractility and relaxation when compared to controls. CONCLUSIONS: These data suggest that particle size and gaseous interactions may play a role in cardiac function decrements one day after exposure. Although FCAPs?+?O? only altered autonomic balance, UFCAPs?+?O? appeared to be more serious by increasing cardiac arrhythmias and causing mechanical decrements. As such, O? appears to interact differently with FCAPs and UFCAPs, resulting in varied cardiac changes, which suggests that the cardiovascular effects of particle-gas co-exposures are not simply additive or even generalizable. Additionally, the mode of toxicity underlying this effect may be subtle given none of the exposures described here impaired post-ischemia recovery.

Project description:This study aimed to investigate the effect of ozone ultrafine bubble water (OUFBW) on the formation and growth of Candida albicans (C. albicans) biofilms and surface properties of denture base resins. OUFBWs were prepared under concentrations of 6 (OUFBW6), 9 (OUFBW9), and 11 ppm (OUFBW11). Phosphate buffered saline and ozone-free electrolyte aqueous solutions (OFEAS) were used as controls. Acrylic resin discs were made according to manufacturer instructions, and C. albicans was initially cultured on the discs for 1.5 h. A colony forming unit (CFU) assay was performed by soaking the discs in OUFBW for 5 min after forming a 24-h C. albicans biofilm. The discs after initial attachment for 1.5 h were immersed in OUFBW and then cultured for 0, 3, and 5 h. CFUs were subsequently evaluated at each time point. Moreover, a viability assay, scanning electron microscopy (SEM), Alamar Blue assay, and quantitative real-time polymerase chain reaction (qRT-PCR) test were performed. To investigate the long-term effects of OUFBW on acrylic resin surface properties, Vickers hardness (VH) and surface roughness (Ra) were measured. We found that OUFBW9 and OUFBW11 significantly degraded the formed 24-h biofilm. The time point CFU assay showed that C. albicans biofilm formation was significantly inhibited due to OUFBW11 exposure. Interestingly, fluorescence microscopy revealed that almost living cells were observed in all groups. In SEM images, the OUFBW group had lesser number of fungi and the amount of non-three-dimensional biofilm than the control group. In the Alamar Blue assay, OUFBW11 was found to suppress Candida metabolic function. The qRT-PCR test showed that OUFBW down-regulated ALS1 and ALS3 expression regarding cell-cell, cell-material adhesion, and biofilm formation. Additionally, VH and Ra were not significantly different between the two groups. Overall, our data suggest that OUFBW suppressed C. albicans growth and biofilm formation on polymethyl methacrylate without impairing surface properties.

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Oxidant-induced epithelial alarmin pathway mediates lung inflammation and functional decline following ultrafine carbon and ozone inhalation co-exposure.

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