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1.
Ecotoxicol Environ Saf ; 214: 112005, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33640725

RESUMO

Exposure to fine particulate matter (PM2.5) is implicated in neurodevelopmental disorders including cognitive decline, attention-deficit/hyperactivity disorder, and autism spectrum disorder. However, the specific molecular mechanisms by which PM2.5 impacts neurodevelopment are poorly understood. Accordingly, in the present study, the role of protein kinase A (PKA)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling in PM2.5-induced neurodevelopmental damage was investigated using primary cultured hippocampal neurons. When hippocampal neurons cultured for 3 days in vitro (DIV3) were exposed to PM2.5 for 24 h and 96 h, neuronal viability decreased by 18.8% and 32.7% respectively, percentage of TUNEL-positive neurons increased by 78.5% and 64.0% separately, caspase-9 expression increased, lower postsynaptic density and shorter active zones were observed by transmission electron microscopy, expression of synapse-related proteins including postsynaptic density-95 (PSD95), growth associated protein-43 (GAP43), and synaptophysin (SYP) were decreased, and the phosphorylation levels of PKA, CREB, and BDNF expression also decreased. However, the PM2.5-induced neuronal damage could be ameliorated or aggravated to varying degrees by up- or down-regulation of the PKA/CREB/BDNF signaling pathway, respectively. Our results indicate that PM2.5 exposure exerts neurodevelopmental toxicity as indicated by lower viability, apoptosis, and synaptic damage in primary cultured hippocampal neurons, and that the PKA/CREB/BDNF pathways could play a vital role in PM2.5-mediated neurodevelopmental toxicity.


Assuntos
Neurônios/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Apoptose , Transtorno do Espectro Autista/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo , Hipocampo/metabolismo , Masculino , Neurônios/metabolismo , Material Particulado/metabolismo , Fosforilação , Ratos , Transdução de Sinais , Sinapses
2.
Ecotoxicol Environ Saf ; 209: 111838, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33387776

RESUMO

Proteomics and bioinformatics were applied to explore PM2.5-induced differentially expressed proteins (DEPs) in hepatocytes (L02 cells) and c-Myc-silenced hepatocytes. L02 cells and c-Myc-silenced hepatocytes were treated with PM2.5 for 24 h. Fifty-two DEPs were screened in L02 hepatocytes, of which 28 were upregulated and 24 were downregulated. Forty-one DEPs were screened in the c-Myc-silenced hepatocytes, of which 31 were upregulated and 10 were downregulated. GO analysis showed that DEPs in L02 cells were mainly concentrated in the cytosol and were involved in biological processes such as the response to metal ions. DEPs in c-Myc-silenced cells were mainly enriched in the extracellular space and were involved in lipoprotein metabolism. KEGG analysis showed that DEPs in L02 cells were mainly involved in arachidonic acid metabolism and mineral absorption. DEPs in c-Myc-silenced cells were mainly enriched in pathways involving nerve absorption, complement and coagulation cascades, and other pathways. Twenty key proteins, including Metallothionein-2A (MT2A), Metallothionein-1X (MT1X), zinc transporter ZIP10 (SLC39A10) and Serine protease 23 (PRSS23) were screened in two groups through analysis of protein-protein interactions. Based on the identification of the selected DEPs, PRSS23 and SLC39A10 might be the potential biomarker of PM2.5-induced carcinogenesis, which provide the scientific basis for further research into the carcinogenic mechanisms of PM2.5.


Assuntos
Hepatócitos/metabolismo , Material Particulado/toxicidade , Proteoma/metabolismo , Biologia Computacional , Material Particulado/metabolismo , Proteômica
3.
Sci Total Environ ; 767: 144485, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33429275

RESUMO

PM2.5 is recognized as an atmospheric pollutant that seriously jeopardizes human health. Emerging evidence indicates that PM2.5 exposure is associated with metabolic disorders. Existing epidemiology and toxicology studies on the health effects of PM2.5 usually focused on its different components and doses, the effects on susceptible populations, or the effects of indoor and outdoor pollution. The underlying mechanisms of exposure time are poorly understood. Liver, as the central organ involved in various metabolisms, has special signaling pathways non-existed in lung and cardiovascular systems. Exacerbation in liver by the prolonged exposure of PM2.5 leads to hepatic function disorder. It is therefore essential to elucidate the mechanism underlying hepatotoxicity after PM2.5 exposure from the perspective of time-response relationship. In this study, targeted metabolomics was utilized to explore the hepatic injury in mice after PM2.5 exposure. Our results showed that prolonged exposure of PM2.5 would aggravate liver metabolic disorders. The metabolic process was divided into three phases. In phase I, it was found that PM2.5 exposure disturbed the hepatic urea synthesis. In phase II, oxidative damages and inflammations obviously occurred in liver, which would further cause neurobehavioral disorders and fat deposits. In phase III, the changes of metabolites and metabolic pathways indicated that the liver has been severely damaged, with the accelerated biosynthesis and fat metabolism. Finally, using ROC analysis coupled with their biological functions, 4 potential biomarkers were screened out, with which we established a method to classify and diagnose the progress of liver damage in mice after PM2.5 exposure. In this paper, we not only established the time-response relationship of PM2.5, but also provided new insights for the classification and prediction of the toxic injury stages in mice liver, which provides a ground work for the future drug intervention to prevent oxidative damage of PM2.5.


Assuntos
Poluentes Atmosféricos , Material Particulado , Poluentes Atmosféricos/metabolismo , Poluentes Atmosféricos/toxicidade , Animais , Metabolismo dos Lipídeos , Fígado/metabolismo , Metabolômica , Camundongos , Material Particulado/metabolismo , Material Particulado/toxicidade
4.
Environ Sci Pollut Res Int ; 28(20): 25819-25829, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33474668

RESUMO

Although positive associations exist between ambient particulate matter (PM2.5; diameter ≤ 2.5 µm) and the morbidity and mortality rates for respiratory diseases, the biological mechanisms of the reported health effects are unclear. Considering that alveolar macrophages (AM) are the main cells responsible for phagocytic clearance of xenobiotic particles that reach the airspaces of the lungs, the purpose of this study was to investigate whether PM2.5 induced AM apoptosis, and investigate its possible mechanisms. Freshly isolated AM from Wistar rats were treated with extracted PM2.5 at concentrations of 33, 100, or 300 µg/mL for 4 h; thereafter, the cytotoxic effects were evaluated. The results demonstrated that PM2.5 induced cytotoxicity by decreasing cell viability and increasing lactate dehydrogenase (LDH) levels in AMs. The levels of reactive oxygen species (ROS) and intracellular calcium cations (Ca2+) markedly increased in higher PM2.5 concentration groups. Additionally, the apoptotic ratio increased, and the apoptosis-related proteins BCL2-associated X (Bax), caspase-3, and caspase-9 were upregulated, whereas B cell lymphoma-2 (Bcl-2) protein levels were downregulated following PM2.5 exposure. Cumulative findings showed that PM2.5 induced apoptosis in AMs through a mitochondrial-mediated pathway, which indicated that PM2.5 plays a significant role in lung injury diseases.


Assuntos
Macrófagos Alveolares , Material Particulado , Animais , Apoptose , Macrófagos Alveolares/metabolismo , Mitocôndrias , Material Particulado/metabolismo , Material Particulado/toxicidade , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
5.
Environ Pollut ; 270: 116242, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33321436

RESUMO

The immune system is one of the primary targets of airborne particulate matter. Recent evidence suggests that mitochondria lie at the center of particulate matter-induced immunotoxicity. Particulate matter can directly interact with mitochondrial components (proteins, lipids, and nucleic acids) and impairs the vital mitochondrial processes including redox mechanisms, fusion-fission, autophagy, and metabolic pathways. These disturbances impede different mitochondrial functions including ATP production, which acts as an important platform to regulate immunity and inflammatory responses. Moreover, the mitochondrial DNA released into the cytosol or in the extracellular milieu acts as a danger-associated molecular pattern and triggers the signaling pathways, involving cGAS-STING, TLR9, and NLRP3. In the present review, we discuss the emerging role of mitochondria in airborne particulate matter-induced immunotoxicity and its myriad biological consequences in health and disease.


Assuntos
Mitocôndrias , Material Particulado , Autofagia , DNA Mitocondrial/metabolismo , Mitocôndrias/metabolismo , Oxirredução , Material Particulado/metabolismo , Material Particulado/toxicidade
6.
Ecotoxicol Environ Saf ; 207: 111281, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32919195

RESUMO

Epidemiological studies of human and animal experiments indicated that gestational exposure to atmospheric pollutants could be followed by the abnormal placental development. However, the effects of this exposure on the placental transportation for nutrients have not been systematically investigated. In this study, fine particulate matters (PM2.5) samples were collected in Taiyuan and pregnant rodent models were administered with 3 mg/kg b.w. PM2.5 by oropharyngeal aspiration every other day starting on embryonic day 0.5 (E0.5). Then the pregnant mice were sacrificed and their placentas were collected at different time points. The results showed that maternal PM2.5 exposure (MPE) disrupted the expression of proliferating cell nuclear antigen (PCNA) at all time points and inhibited the cell proliferation in placenta. Following that, the capacity for placental nutrient transport was impaired. The changes at E18.5 were observed most significantly, showing the altered mRNA expression of amino acid, long-chain polyunsaturated fatty acid (LCPUFA), glucose and folate transporters. In addition, the glycogen content was elevated at E18.5, and the triglyceride content was increased at E13.5 and E15.5 and decreased at E18.5 in the placenta after MPE. In a word, the adverse effect induced by MPE revealed that MPE led tothe disruption on the nutrient supply to the developing fetus via modulating the abundance of placental nutrient transporters (PNT).


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Materna/efeitos adversos , Nutrientes/metabolismo , Material Particulado/toxicidade , Placenta/efeitos dos fármacos , Poluentes Atmosféricos/metabolismo , Aminoácidos/metabolismo , Animais , Transporte Biológico , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/metabolismo , Feminino , Glucose/metabolismo , Glicogênio/metabolismo , Humanos , Troca Materno-Fetal/efeitos dos fármacos , Camundongos , Material Particulado/metabolismo , Placenta/metabolismo , Placenta/patologia , Gravidez
7.
Ecotoxicol Environ Saf ; 205: 111327, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961493

RESUMO

Exposure to PM2.5 can cause serious harm to the respiratory system. Until now, although many toxicological studies have shown that pulmonary fibrosis can be caused by long-term PM2.5 exposure, there is no evidence that Endothelial-Mesenchymal Transition (EndMT) can trigger the process of pulmonary fibrosis after exposure. LncRNAs are a class of non-coding RNAs detected in mammalian cells. Nevertheless, researchers have not found whether lncRNAs participate in PM2.5 induced EndMT during pathophysiological duration. The Balb/c mouse model was exposed to PM2.5 for 4 months by dynamic intoxication. The levels of specific endothelial and mesenchymal markers were evaluated by molecular biology experiments to elucidate the mechanisms of EndMT induced by PM2.5 in lung tissues. LncRNA microarray analysis of the established mouse model of PM2.5 exposure was performed. Based on a bioinformatics analysis and RT-qPCR analysis, lncRNA Gm16410 attracted our attention. The change of lncRNA Gm16410 in mouse pulmonary vascular endothelial cells (MHCs) exposed to PM2.5 was verified, and the mechanism of lncRNA Gm16410 in EndMT was discussed. The changes of cell function were evaluated by cell migration and proliferation experiments. The molecular biology experiments proved that PM2.5 induced EndMT by activating the TGF-ß1/Smad3/p-Smad3 pathway in vitro. The relationship of EndMT and lncRNA Gm16410 was verified in mouse lung tissues and MHC cells by PM2.5 exposure. The involvement of lncRNA Gm16410 in PM2.5-induced EndMT highlights the potential of lncRNA to promote pulmonary fibrosis under environmental pollution.


Assuntos
Material Particulado/toxicidade , RNA Longo não Codificante/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Camundongos , Material Particulado/metabolismo , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3 , Fator de Crescimento Transformador beta1/metabolismo
8.
Gene ; 740: 144570, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32165298

RESUMO

Recent studies have found multiple single nucleotide variants (SNVs) associated with DNA damage. However, previous association analysis may ignore the potential interaction effects between SNVs. Therefore, we used an improved random forest (RF) analysis to identify the SNVs related to personal DNA damage in exon-focused genome-wide association study (GWAS). A total of 301 subjects from three independent centers (Zhuhai, Wuhan, and Tianjin) were retained for analysis. An improved RF procedure was used to systematically screen key SNVs associated with DNA damage. Furthermore, we used genetic risk score (GRS) and mediation analysis to investigate the integrative effect and potential mechanism of these genetic variants on DNA damage. Besides, gene set enrichment analysis was conducted to identify the pathways enriched by key SNVs using the Data-driven Expression Prioritized Integration for Complex Traits (DEPICT). Finally, a set of 24 SNVs with the lowest mean square errors (MSE) were identified by improved RF analysis. Both weighted and unweighted GRSs were associated with increased DNA damage levels (Pweight < 0.001 and Punweight < 0.001). Gene set enrichment analysis indicated that these loci were significantly enriched in several biological features associated with DNA damage. These findings suggested the role of SNVs in modifying DNA damage levels. It may be convincing that this improved RF analysis can effectively identify SNVs associated with DNA damage levels.


Assuntos
Dano ao DNA , Material Particulado/toxicidade , China , Dano ao DNA/genética , Dano ao DNA/fisiologia , Interpretação Estatística de Dados , Humanos , Material Particulado/sangue , Material Particulado/metabolismo , Polimorfismo de Nucleotídeo Único
9.
Sci Rep ; 10(1): 3387, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32099047

RESUMO

The extent to which commercially important Nephrops norvegicus lobsters feed on particulates in the wild is unknown, even though this could be an important way for burrow-dwelling females to avoid starvation during the long breeding season. This was investigated using δ13C and δ15N isotopic signatures in tissues with long and short turnover rates to provide diet discrimination and compare this between males and females. Secondary objectives examined size-related differences and calculated the trophic position based on the new results. Almost half the diet (47%) was made up of suspended particulate organic matter (POMsusp) alone. Fish was another important item in the diet, with plankton and invertebrate sources coming much lower down in dietary importance. Significantly more suspension feeding was observed in small or medium sized individuals than large ones in both sexes. However, there were no sex-related patterns, despite females being restricted to burrows for part of the analysis period. Female diet was almost identical to males and POMsusp comprised a large component of the diet in both sexes. The trophic position was estimated at 2.94 ± 0.16 (mean ± SD), which was at the lower end of the range reported in previous studies (2.60 to 4.32).


Assuntos
Dieta , Nephropidae/metabolismo , Material Particulado/metabolismo , Animais , Teorema de Bayes , Isótopos de Carbono/química , Isótopos de Carbono/metabolismo , Dieta/veterinária , Feminino , Masculino , Isótopos de Nitrogênio/química , Isótopos de Nitrogênio/metabolismo , Material Particulado/análise , Estações do Ano
10.
Environ Pollut ; 256: 113342, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31676093

RESUMO

PM2.5 exposure aggravates type 2 diabetes, in which inflammatory factors play an important role. In this study, we aimed to explore the mechanisms responsible for aggravating diabetes after PM2.5 exposure, and study the roles of inflammatory factors in insulin-resistant type 2 diabetes. Our study indicated that short-time PM2.5 exposure enhances insulin resistance in type 2 diabetic rats and significantly raises inflammatory factors, including IL-6, TNF-α, and MCP-1, in lungs. However, we found that of these inflammatory factors only IL-6 levels are elevated in blood, liver, adipose tissue, and macrophages, but not in skeletal muscle. IL-6 induced activation of the STAT3/SOCS3 pathway in liver, but not other downstream pathways including STAT1, ERK1/2, and PI3K. Both STAT3 inhibition and IL-6 neutralization effectively alleviated the disorders of glucose metabolism after PM2.5 exposure. Taken together, this suggests that the systemic increase in IL-6 may play an important role in the deterioration of the type 2 diabetes via IL-6/STAT3/SOCS3 pathway in liver after short-time exposure to PM2.5. Besides, we unexpectedly found a stronger resistance to the PM2.5 exposure-induced increase in IL-6 in skeleton muscle than those of many other tissues.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Interleucina-6/sangue , Material Particulado/toxicidade , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/imunologia , Material Particulado/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais
11.
Chemosphere ; 239: 124734, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31494317

RESUMO

Dam construction and fish culture can change the biogeochemical processes in river, yet their impact on the spectral properties of particulate organic matter (POM) remains to be studied. This was investigated in a reservoir-type river (Minjiang river, SE China) using absorption spectroscopy and fluorescence excitation-emission matrices-parallel factor analysis (EEMs-PARAFAC). Five fluorescent components were identified from POM with PARAFAC. Four components C1-C4 were affected by the seasonal variations of rainfall and runoff, indicating the influences of hydrological condition and terrestrial inputs. The Chlorophyll a concentration (Chl a) correlated significantly with the humic-like C3 (p < 0.05) and the protein-like C4 (p < 0.01), indicating phytoplankton was an important source of C3 and C4. The Chl a and fluorescence intensities of C3-C4 were higher in the fish culture zones than in other areas, and the absorption coefficient a300 and C1-C4 were lower downstream the dam. These results indicated that fish farming in the reservoir probably promoted the production of POM. The a300 and C1 per unit mass of suspended particulate matter (a300/TSM and C1/TSM) correlated significantly with the median particle size (p < 0.01), which might be related to the contribution of micro-phytoplankton. The absorption spectra of POM showed a shoulder peak at ∼280 nm, and its intensity correlated significantly and positively with Chl a (p < 0.01). These results indicated that the peak was probably derived from phytoplankton production. Our results have implications for better understanding the influences of human activities on the dynamics of river POM.


Assuntos
Pesqueiros , Material Particulado/metabolismo , Rios/química , Espectrometria de Fluorescência/métodos , China , Clorofila A/metabolismo , Monitorização de Parâmetros Ecológicos , Monitoramento Ambiental/métodos , Análise Fatorial , Fluorescência , Tamanho da Partícula , Material Particulado/análise , Fitoplâncton , Chuva , Estações do Ano
12.
Sci Rep ; 9(1): 18178, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796766

RESUMO

Diesel exhaust particles (DEPs) are major air pollutants that lead to numerous human disorders, especially pulmonary diseases, partly through the induction of oxidative stress. Resveratrol is a polyphenol that ameliorates the production of reactive oxygen species (ROS) and delays aging-related processes. Herein we studied the cytoprotective effect of resveratrol on DEP-exposed human lung cells in a factorial experimental design. This work investigates biophysical features including cellular compositions and biomechanical properties, which were measured at the single-cell level using confocal Raman microspectroscopy (RM) and atomic force microscopy (AFM), respectively. Principal component analysis (PCA), hierarchical cluster analysis (HCA) and partial least square regression (PLS) analysis were applied to analyze Raman spectra with and without resveratrol protection. The health status of individual cells could be effectively predicted using an index derived from characteristic Raman spectral peak (e.g., 1006 cm-1) based on PLS model. AFM measurements indicated that cellular adhesion force was greatly reduced, while Young's modulus was highly elevated in resveratrol treated DEP-exposed cells. Anti-oxidant resveratrol reduced DEP-induced ROS production and suppressed releases of several cytokines and chemokines. These findings suggest resveratrol may enhance resistance of human lung cells (e.g., SAEC) to air pollutants (e.g. DEPs).


Assuntos
Pulmão/efeitos dos fármacos , Material Particulado/metabolismo , Material Particulado/toxicidade , Resveratrol/farmacologia , Emissões de Veículos/toxicidade , Poluentes Atmosféricos/metabolismo , Poluentes Atmosféricos/toxicidade , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Pulmão/metabolismo , Espécies Reativas de Oxigênio/metabolismo
13.
Res Rep Health Eff Inst ; (197): 1-57, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31872749

RESUMO

INTRODUCTION: Many studies have established associations between exposure to air pollution, or atmospheric particulate matter (PM), and adverse health effects. An increasing array of studies have suggested oxidative stress as a possible mechanism by which PM-induced health effects arise, and as a result, many chemical and cellular assays have been developed to study PM-induced oxidant production. Although significant progress has been made in recent years, there are still many gaps in this area of research that have not been addressed. Many prior studies have focused on the aerosol of primary origin (e.g., the aerosol emitted from combustion engines) although the aerosol formed from the oxidation of volatile species, secondary organic aerosol (SOA), has been shown to be the predominant type of aerosol even in urban areas. Current SOA health studies are limited in number, and as such, the health effects of SOA are poorly characterized. Also, there is a lack of perspective in terms of the relative toxicities of different SOA systems. Additionally, although chemical assays have identified some SOA constituents associated with adverse health endpoints, the applicability of these results to cellular responses has not been well established. SPECIFIC AIMS: The overall objective of this study was to better understand the oxidative properties of different types and components of PM mixtures (especially SOA) through systematic laboratory chamber experiments and ambient field studies. The study had four specific aims.1 To develop a cellular assay optimized for measuring reactive oxygen and nitrogen species (ROS/RNS) production resulting from PM exposure and to identify a robust parameter that could represent ROS/RNS levels for comparison with different endpoints.2 To identify ambient PM components associated with ROS/RNS production and evaluate whether results from chemical assays represented cellular responses in terms of ROS/RNS production.3 To investigate and provide perspective on the relative toxicities of SOA formed from common biogenic and anthropogenic precursors under different conditions (e.g., humidity, nitrogen oxides [NOx], and redox-active metals) and identify bulk aerosol properties associated with cellular responses.4 To investigate the effects of photochemical aging on aerosol toxicity. METHODS: Ambient PM samples were collected from urban and rural sites in the greater Atlanta area as part of the Southeastern Center for Air Pollution and Epidemiology (SCAPE) study between June 2012 and October 2013. The concentrations of water-soluble species (e.g., water-soluble organic carbon [WSOC], brown carbon [Br C], and metals) were characterized using a variety of instruments. Samples for this study were chosen to span the observed range of dithiothreitol (DTT) activities.Laboratory studies were conducted in the Georgia Tech Environmental Chamber (GTEC) facility in order to generate SOA under well-controlled photooxidation conditions. Precursors of biogenic origin (isoprene, α-pinene, and ß-caryophyllene) and anthropogenic origin (pentadecane, m-xylene, and naphthalene) were oxidized under various formation conditions (dry vs. humid, NOx, and ammonium sulfate vs. iron sulfate seed particles) to produce SOA of differing chemical composition and mass loading. For the naphthalene system, a series of experiments were conducted with different initial hydrocarbon concentrations to produce aerosols with various degree of oxidation. A suite of instruments was utilized to monitor gas- and particle-phase species. Bulk aerosol properties (e.g., O:C, H:C, and N:C ratios) were measured using a high-resolution time-of-flight aerosol mass spectrometer. Filter samples were collected for chemical oxidative potential and cellular measurements. For the naphthalene system, multiple filter samples were collected over the course of a single experiment to collect aerosols of different photochemical aging.For all filter samples, chemical oxidative potentials were determined for water-soluble extracts using a semiautomated DTT assay system. Murine alveolar macrophages and neonatal rat ventricular myocytes were also exposed to PM samples extracted in cell culture medium to investigate cellular responses. ROS/RNS production was detected using the intracellular ROS/RNS probe, carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy-H2DCFA), whereas cellular metabolic activity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Finally, cytokine production, that is, secreted levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were measured post-exposure using an enzyme-linked immunosorbent assay (ELISA). To identify PM constituents associated with oxidative properties, linear regressions between oxidative properties (cellular responses or DTT activity) and aerosol composition (metals, elemental ratios, etc.) were evaluated using Pearson's correlation coefficient, where the significance was determined using multiple imputation and evaluated using a 95% confidence interval. RESULTS: We optimized several parameters for the ROS/RNS assay, including cell density (2 × 104 cells/well for macrophages and 3.33 × 104 cells/well for cardiomyocytes), probe concentration (10 µM), and sample incubation time (24 hours). Results from both ambient and laboratory-generated aerosols demonstrate that ROS/RNS production was highly dose-dependent and nonlinear with respect to PM dose. Of the dose-response metrics investigated in this study (maximum response, dose at which the response is 10% above the baseline [threshold], dose at which 50% of the response is attained [EC50], rate at which the maximum response is attained [Hill slope], and area under the dose-response curve [AUC]), we found that the AUC was the most robust parameter whose informativeness did not depend on dose range.A positive, significant correlation was observed between ROS/RNS production as represented by AUC and chemical oxidative potential as measured by DTT for ambient samples collected in summer. Conversely, a relatively constant AUC was observed for ambient samples collected in winter regardless of the corresponding DTT activity. We also identified several PM constituents (WSOC, BrC, iron, and titanium) that were significantly correlated with AUC for summer samples. The strong correlation between organic species and ROS/RNS production highlights a need to understand the contribution of organic aerosols to PM-induced health effects. No significant correlations were observed for other ROS/RNS metrics or PM constituents, and no spatial trends were observed.For laboratory-generated aerosol, precursor identity influenced oxidative potentials significantly, with isoprene and naphthalene SOA having the lowest and highest DTT activities, respectively. Both precursor identity and formation condition significantly influenced inflammatory responses induced by SOA exposure, and several response patterns were identified for SOA precursors whose photooxidation products share similar carbon-chain length and functionalities. The presence of iron sulfate seed particles did not have an apparent effect on oxidative potentials; however, a higher level of ROS/RNS production was observed for all SOA formed in the presence of iron sulfate compared with ammonium sulfate. We also identified a significant positive correlation between ROS/RNS production and average carbon oxidation state, a bulk aerosol property. It may therefore be possible to roughly estimate ROS/RNS production using this property, which is readily obtainable. This correlation may have significant implications as aerosols have an atmospheric lifetime of a week, during which average carbon oxidation state increases because of atmospheric photochemical aging. Our results suggest that aerosols might become more toxic as they age in the atmosphere. Finally, in the context of ambient samples, laboratory-generated SOA induced comparable or higher levels of ROS/RNS. Oxidative potentials for all laboratory SOA systems, with the exception of naphthalene (which was higher), were all comparable with oxidative potentials observed in ambient samples.


Assuntos
Aerossóis/metabolismo , Aerossóis/farmacologia , Bioensaio , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/metabolismo , Material Particulado/farmacologia , Humanos , Laboratórios , Material Particulado/análise
14.
Res Rep Health Eff Inst ; (198): 1-54, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31872748

RESUMO

INTRODUCTION: Airborne fine particulate matter (PM2.5; particulate matter ≤ 2.5 µm in aerodynamic diameter) plays a key role in air quality, climate, and public health. Globally, the largest mass fraction of PM2.5 is organic, dominated by secondary organic aerosol (SOA) formed from atmospheric oxidation of volatile organic compounds (VOCs). Isoprene from vegetation is the most abundant nonmethane VOC emitted into Earth's atmosphere. Isoprene has been recently recognized as one of the major sources of global SOA production that is enhanced by the presence of anthropogenic pollutants, such as acidic sulfate derived from sulfur dioxide (SO2), through multiphase chemistry of its oxidation products. Considering the abundance of isoprene-derived SOA in the atmosphere, understanding mechanisms of adverse health effects through inhalation exposure is critical to mitigating its potential impact on public health. Although previous studies have examined the toxicological effects of certain isoprene-derived gas-phase oxidation products, to date, no systematic studies have examined the potential toxicological effects of isoprene-derived SOA, its constituents, or its SOA precursors on human lung cells. SPECIFIC AIMS: The overall objective of this study was to investigate the early biological effects of isoprene-derived SOA and its subtypes on BEAS-2B cells (a human bronchial epithelial cell line), with a particular focus on the alteration of oxidative stress- and inflammation-related genes. To achieve this objective, there were two specific aims.1. Examine toxicity and early biological effects of SOA derived from the photochemical oxidation of isoprene, considering both urban and downwind-urban types of chemistry.2. Examine toxicity and early biological effects of SOA derived directly from downstream oxidation products of isoprene (i.e., epoxides and hydroperoxides). METHODS: Isoprene-derived SOA was first generated by photooxidation of isoprene under natural sunlight in the presence of nitric oxide (NO) and acidified sulfate aerosols. Experiments were conducted in a 120-m3 outdoor Teflon-film chamber located on the roof of the Gillings School of Global Public Health, University of North Carolina at Chapel Hill (UNC-Chapel Hill). BEAS-2B cells were exposed to chamber- generated isoprene-derived SOA using the Electrostatic Aerosol in Vitro Exposure System (EAVES). This approach allowed us to generate atmospherically relevant compositions of isoprene-derived SOA and to examine its toxicity through in vitro exposures at an air-liquid interface, providing a more biologically relevant exposure model. Isoprene-derived SOA samples were also collected, concurrently with EAVES sampling, onto Teflon membrane filters for in vitro resuspension exposures and for analysis of aerosol chemical composition by gas chromatography/electron ionization-quadrupole mass spectrometry (GC/EI-MS) with prior trimethylsilylation and ultra-performance liquid-chromatography coupled to high-resolution quadrupole time-of-flight mass spectrometry equipped with electrospray ionization (UPLC/ESI-HR-QTOFMS). Isoprene-derived SOA samples were also analyzed by the dithiothreitol (DTT) assay in order to characterize their reactive oxygen species (ROS)-generation potential.Organic synthesis of known isoprene-derived SOA precursors, which included isoprene epoxydiols (IEPOX), methacrylic acid epoxide (MAE), and isoprene-derived hydroxyhydroperoxides (ISOPOOH), was conducted in order to isolate major isoprene-derived SOA formation pathways from each other and to determine which of these pathways (or SOA types) is potentially more toxic. Since IEPOX and MAE produce SOA through multiphase chemistry onto acidic sulfate aerosol, dark reactive uptake experiments of IEPOX and MAE in the presence of acidic sulfate aerosol were performed in a 10-m3 flexible Teflon indoor chamber at UNC-Chapel Hill. Since the generation of SOA from ISOPOOH (through a non-IEPOX route) requires a hydroxyl radical (•OH)-initiated oxidation, ozonolysis of tetramethylethylene (TME) was used to form the needed •OH radicals in the indoor chamber. The resultant low-volatility multifunctional hydroperoxides condensed onto nonacidified sulfate aerosol, yielding the ISOPOOH-derived SOA needed for exposures. Similar to the outdoor chamber SOAs, IEPOX, MAE- and ISOPOOH-derived SOAs were collected onto Teflon membrane filters and were subsequently chemically characterized by GC/EI-MS and UPLC/ESI-HR-QTOFMS as well as for ROS-generation potential using the DTT assay. These filters were also used for resuspension in vitro exposures.By conducting gene expression profiling, we provided mechanistic insights into the potential health effects of isoprene-derived SOA. First, gene expression profiling of 84 oxidative stress- and 249 inflammation-associated human genes was performed for cells exposed to isoprene-derived SOA generated in our outdoor chamber experiments in EAVES or by resuspension. Two pathway-focused panels were utilized for this purpose: (1) nCounter GX Human Inflammation Kit comprised of 249 human genes (NanoString), and (2) Human Oxidative Stress Plus RT2 Profiler PCR Array (Qiagen) comprised of 84 oxidative stress-associated genes. We compared the gene expression levels in cells exposed to SOA generated in an outdoor chamber from photochemical oxidation of isoprene in the presence of NO and acidified sulfate seed aerosol to cells exposed to a dark control mixture of isoprene, NO, and acidified sulfate seed aerosol to isolate the effects of the isoprene-derived SOA on the cells using the EAVES and resuspension exposure methods. Pathway-based analysis was performed for significantly altered genes using the ConsensusPathDB database, which is a database system for the integration of human gene functional interactions to provide biological pathway information for a gene set of interest. Pathway annotation was performed to provide biological pathway information for each gene set. The gene-gene interaction networks were constructed and visualized using the GeneMANIA Cytoscape app (version 3.4.1) to predict the putative function of altered genes. Lastly, isoprene-derived SOA collected onto filters was used in resuspension exposures to measure select inflammatory biomarkers, including interleukin 8 (IL-8) and prostaglandin-endoperoxide synthase 2 (PTGS2) genes, in BEAS-2B cells to ensure that effects observed from EAVES exposures were attributable to particle-phase organic products. Since EAVES and resuspension exposures compared well, gene expression profiling for IEPOX-, MAE- and ISOPOOH-derived SOA were conducted using only resuspension exposures. RESULTS AND CONCLUSIONS: Chemical characterization coupled with biological analyses show that atmospherically relevant compositions of isoprene-derived SOA alter the levels of 41 oxidative stress-related genes. Of the different composition types of isoprene-derived SOA, MAE- and ISOPOOH-derived SOA altered the greatest number of genes, suggesting that carbonyl and hydroperoxide functional groups are oxidative stress promoters. Taken together, the different composition types accounted for 34 of the genes altered by the total isoprene-derived SOA mixture, while 7 remained unique to the total mixture exposures, indicating that there is either a synergistic effect of the different isoprene-derived SOA components or an unaccounted component in the mixture.The high-oxides of nitrogen (NOx) regime, which yielded MAE- and methacrolein (MACR)-derived SOA, had a higher ROS-generation potential (as measured by the DTT assay) than the low- NOx regime, which included IEPOX- and isoprene-derived SOA. However, ISOPOOH-derived SOA, which also formed in the low- NOx regime, had the highest ROS-generation potential, similar to 1,4-naphthoquinone (1,4-NQ). This suggests that aerosol-phase organic peroxides contribute significantly to particulate matter (PM) oxidative potential. MAE- and MACR- derived SOA showed equal or greater ROS-generation potential than was reported in prior UNC-Chapel Hill studies on diesel exhaust PM, highlighting the importance of a comprehensive investigation of the toxicity of isoprene-derived SOA. Notably, ISOPOOH-derived SOA was one order of magnitude higher in ROS-generation potential than diesel exhaust particles previously examined at UNC-Chapel Hill. As an acellular assay, the DTT assay may not be predictive of oxidative stress; therefore, we also focused on the gene expression results from the cellular exposures.We have demonstrated that the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the redox-sensitive activation protein-1 (AP-1) transcription factor networks have been significantly altered upon exposure to isoprene-derived SOA. The identification of Nrf2 pathway in cells exposed to isoprene-derived SOA is in accordance with our findings using the DTT assay, which measures the thiol reactivity of PM samples as a surrogate for their ROS-generation potential. Specifically, our results point to the cysteine-thiol modifications within cells that lead to activation of Nrf2-related gene expression.However, based on our gene expression results showing no clear relationship between DTT activity and the number of altered oxidative stress-related genes, the DTT activity of isoprene-derived SOA may not be directly indicative of toxicity relative to other SOA types. While activation of Nrf2-associated genes has been identified with responses to oxidative stress and linked to traffic related air pollution exposure in both toxicological and epidemiological studies, their implicit involvement in this study suggests that activation of Nrf2-related gene expression may occur with exposures to all sorts of PM types.By controlling the exposure time, method, and dose we demonstrated that among the SOA derived from previously identified individual precursors of isoprene-derived SOA, ISOPOOH-derived SOA alters moreoxidative stress related genes than does IEPOX-derived SOA, but fewer than MAE-derived SOA. This suggests that the composition of MAE-derived SOA may be the greatest contributor to alterations of oxidative stress-related gene expression observed due to isoprene-derived SOA exposure. Further study on induced levels of protein expression and specific toxicological endpoints is necessary to determine if the observed gene expression changes lead to adverse health effects. In addition, such studies have implications for pollution-control strategies because NOx and SO2 are controllable pollutants that can alter the composition of SOA, and in turn alter its effects on gene expression. The mass fraction of different components of atmospheric isoprene derived SOA should be considered, but altering the fraction of high- NOx isoprene-derived SOA (e.g., MAE derived SOA) may yield greater changes in gene expression than altering the fraction of low- NOx isoprene derived SOA types (ISOPOOH- or IEPOX-derived SOA). Finally, this study confirms that total isoprene-derived SOA alters the expression of a greater number of genes than does SOA derived from the tested precursors. This warrants further work to determine the underlying explanation for this observation, which may be uncharacterized components of isoprene-derived SOA or the potential for synergism between the studied components.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Butadienos/metabolismo , Hemiterpenos/metabolismo , Oxidantes Fotoquímicos/metabolismo , Material Particulado/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos
15.
Oxid Med Cell Longev ; 2019: 2492368, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885780

RESUMO

Oxidative stress has been proven as one of the most critical regulatory mechanisms involved in fine Particulate Matter- (PM2.5-) mediated toxicity. For a better understanding of the underlying mechanisms that enable oxidative stress to participate in PM2.5-induced toxic effects, the current study explored the effects of oxidative stress induced by PM2.5 on UPR and lifespan in C. elegans. The results implicated that PM2.5 exposure induced oxidative stress response, enhanced metabolic enzyme activity, activated UPR, and shortened the lifespan of C. elegans. Antioxidant N-acetylcysteine (NAC) could suppress the UPR through reducing the oxidative stress; both the antioxidant NAC and UPR inhibitor 4-phenylbutyric acid (4-PBA) could rescue the lifespan attenuation caused by PM2.5, indicating that the antioxidant and moderate proteostasis contribute to the homeostasis and adaptation to oxidative stress induced by PM2.5.


Assuntos
Caenorhabditis elegans/patogenicidade , Longevidade/efeitos dos fármacos , Material Particulado/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Animais , Linhagem Celular , Estresse Oxidativo , Espécies Reativas de Oxigênio
16.
Artigo em Inglês | MEDLINE | ID: mdl-31731429

RESUMO

Tuberculosis (TB) and air pollution both contribute significantly to the global burden of disease. Epidemiological studies show that exposure to household and urban air pollution increase the risk of new infections with Mycobacterium tuberculosis (M.tb) and the development of TB in persons infected with M.tb and alter treatment outcomes. There is increasing evidence that particulate matter (PM) exposure weakens protective antimycobacterial host immunity. Mechanisms by which exposure to urban PM may adversely affect M.tb-specific human T cell functions have not been studied. We, therefore, explored the effects of urban air pollution PM2.5 (aerodynamic diameters ≤2.5µm) on M.tb-specific T cell functions in human peripheral blood mononuclear cells (PBMC). PM2.5 exposure decreased the capacity of PBMC to control the growth of M.tb and the M.tb-induced expression of CD69, an early surface activation marker expressed on CD3+ T cells. PM2.5 exposure also decreased the production of IFN-γ in CD3+, TNF-α in CD3+ and CD14+ M.tb-infected PBMC, and the M.tb-induced expression of T-box transcription factor TBX21 (T-bet). In contrast, PM2.5 exposure increased the expression of anti-inflammatory cytokine IL-10 in CD3+ and CD14+ PBMC. Taken together, PM2.5 exposure of PBMC prior to infection with M.tb impairs critical antimycobacterial T cell immune functions.


Assuntos
Mycobacterium tuberculosis/imunologia , Material Particulado/análise , Material Particulado/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Adulto , Poluição do Ar/análise , Cidades , Citocinas/metabolismo , Testes Diagnósticos de Rotina , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Environ Pollut ; 255(Pt 1): 113366, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668954

RESUMO

Air pollution is one of the leading preventable threats to public health. Emerging evidence indicates that exposure to environmental stressors is associated with abnormal foetal development. However, how prenatal exposure to diesel exhaust PM2.5 (DEP) predisposes adult offspring to the development of non-alcoholic fatty liver disease (NAFLD) remains unclear. To examine this, C57BL/6J mice were exposed to DEP or a vehicle before conception and during pregnancy and fed normal chow or a high-fat diet. Then, the hepatic fatty accumulation in the adult male offspring and possible molecular mechanisms were assessed. Our data showed that prenatal exposure to DEP on normal chow led to hepatic steatosis in adult male offspring with normal liver function. However, prenatal DEP exposure relieved the hepatic steatosis and liver function in offspring of mice fed a high-fat diet. Furthermore, prenatal exposure to DEP on normal chow increased lipogenesis and worsened fatty acid oxidation. The counteractive effect of prenatal DEP exposure on high-fat-diet-induced hepatic steatosis was produced through upregulated adenosine 5'-monophosphate-activated protein kinase, and this improved lipogenesis and fatty acid oxidation. Collectively, prenatal exposure to DEP programmed the development of NAFLD differently in the adult male offspring of mice fed normal chow and a high-fat diet, showing the pleotrophic effects of exposure to adverse environmental factors in early life.


Assuntos
Dieta Hiperlipídica , Hepatopatia Gordurosa não Alcoólica , Material Particulado/toxicidade , Emissões de Veículos/toxicidade , Crianças Adultas , Poluição do Ar , Animais , Feminino , Desenvolvimento Fetal , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Material Particulado/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo
18.
Proc Natl Acad Sci U S A ; 116(46): 23309-23316, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31666322

RESUMO

The recycling of particulate organic matter (POM) by microbes is a key part of the global carbon cycle. This process is mediated by the extracellular hydrolysis of polysaccharides, which can trigger social behaviors in bacteria resulting from the production of public goods. Despite the potential importance of public good-mediated interactions, their relevance in the environment remains unclear. In this study, we developed a computational and experimental model system to address this challenge and studied how the POM depolymerization rate and its uptake efficiency (2 main ecosystem function parameters) depended on social interactions and spatial self-organization on particle surfaces. We found an emergent trade-off between rate and efficiency resulting from the competition between oligosaccharide diffusion and cellular uptake, with low rate and high efficiency being achieved through cell-to-cell cooperation between degraders. Bacteria cooperated by aggregating in cell clusters of ∼10 to 20 µm, in which cells were able to share public goods. This phenomenon, which was independent of any explicit group-level regulation, led to the emergence of critical cell concentrations below which degradation did not occur, despite all resources being available in excess. In contrast, when particles were labile and turnover rates were high, aggregation promoted competition and decreased the efficiency of carbon use. Our study shows how social interactions and cell aggregation determine the rate and efficiency of particulate carbon turnover in environmentally relevant scenarios.


Assuntos
Interações Microbianas , Modelos Biológicos , Compostos Orgânicos/metabolismo , Material Particulado/metabolismo , Organismos Aquáticos/metabolismo , Ciclo do Carbono
19.
Environ Pollut ; 255(Pt 3): 113331, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31614245

RESUMO

We previously found that folic acid (FA) attenuated cardiac defects in zebrafish embryos exposed to extractable organic matter (EOM) from PM2.5, but the underlining mechanisms remain to be elucidated. Since DNA methylation is crucial to cardiac development, we hypothesized that EOM-induced aberrant DNA methylation changes could be diminished by FA supplementation. In this study, zebrafish embryos were exposed to EOM in the absence or presence of FA. Genomic-wide DNA methylation analysis identified both DNA hypo- and hyper-methylation changes in CCGG sites in zebrafish embryos exposed to EOM, which were attenuated by FA supplementation. We identified a total of 316 genes with extensive DNA methylation changes in EOM samples but little or no DNA methylation changes in EOM plus FA samples. The genes were involved in critical cellular processes and signaling pathways important for embryo development. In addition, the EOM-decreased SAM/SAH ratio was counteracted by FA supplementation. Furthermore, FA attenuated the EOM-induced changes in the expression of genes involved in the regulation of DNA methylation and in folate biosynthesis. In conclusion, our data suggest that FA supplementation protected zebrafish embryos from the cardiac developmental toxicity of PM2.5 by alleviating EOM-induced DNA methylation changes.


Assuntos
Ácido Fólico/metabolismo , Material Particulado/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Metilação de DNA/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Coração/efeitos dos fármacos , Material Particulado/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo
20.
Environ Sci Pollut Res Int ; 26(31): 32476-32487, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31617135

RESUMO

Particulate matter (PM) contains different chemical substances that have been associated with health effects and an increased risk of mortality due to their toxicity. In this study, fine particulate matter (PM2.5) samples were collected in a region with rural characteristics (Seropédica (Se)) and another with some industries (Duque de Caxias (DC)) (Brazil, RJ). Rats were exposed to PM2.5 extracts daily for 25 days at different dilutions: 10×, 5×, and a concentrated solution (CS). Biochemical analyses were investigated for total antioxidant capacity (ACAP), lipid peroxidation (LPO) levels, reduced glutathione (GSH) concentration, activity of glutamate cysteine ligase (GCL), and activity of glutathione S-transferase (GST). The liver showed a significant increase in GCL (DC-5×, DC-CS and Se-CS) and GST activities (DC-CS and Se-CS) in both regions when compared to the control group. In the renal cortex, GCL activity decreased in most of the tested groups while GST activity increased only in the 5× groups of both regions (DC and Se). In the renal medulla, GCL activity decreased for Se-10× and DC-CS but increased for Se-5×, and GST activity increased in the Se-10×, DC-5×, and DC-CS groups. Lung GCL increased in all groups for both regions. Moreover, this organ also showed an increase in GST activity when higher metal concentrations were present (5× and CS). TBARS levels were increased for all tissues in most tested concentrations. These data indicate that soluble compounds (e.g., metals) from PM2.5 sampled in areas with different pollution indexes can change the redox status and cause damage to different tissues.


Assuntos
Antioxidantes/metabolismo , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Animais , Glutamato-Cisteína Ligase , Glutationa Transferase/metabolismo , Metais/química , Material Particulado/química , Ratos , Substâncias Reativas com Ácido Tiobarbitúrico/química
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