Nontargeted Identification of Organic Components in Fine Particulate Matter Related to Lung Tumor Metastasis Based on an Adverse Outcome Pathway Strategy.

Emerging studies implicate fine particulate matter (PM2.5) and its organic components (OCs) as urgent hazard factors for lung cancer progression in nonsmokers. Establishing the adverse outcome pathway (AOP)-directed nontargeted identification method, this study aimed to explore whether PM2.5 exposure in coal-burning areas promoted lung tumor metastasis and how we identify its effective OCs to support traceability and control of regional PM2.5 pollution. First, we used a nude mouse model of lung cancer for PM2.5 exposure and found that the exposure significantly promoted the hematogenous metastases of A549-Luc cells in lung tissues and the adverse outcomes (AOs), with key events (KEs) including the changed expression of epithelial-mesenchymal transition (EMT) markers, such as suppression of E-cad and increased expression of Fib. Subsequently, using AOs and KEs as adverse outcome directors, we identified a total of 35 candidate chemicals based on the in vitro model and nontargeted analysis. Among them, tributyl phosphate (C12H27O4P), 2-bromotetradecane (C14H29Br), and methyl decanoate (C11H22O2) made greater contributions to the AOs. Finally, we clarified the interactions between these OCs and EMT-activating transcription factors (EMT-ATFs) as the molecular initiation event (MIE) to support the feasibility of the above identification strategy. The present study updates a new framework for identifying tumor metastasis-promoting OCs in PM2.5 and provides solid data for screening out chemicals that need priority control in polluted areas posing higher lung cancer risk.

Multilevel Screening Strategy to Identify the Hydrophobic Organic Components of Ambient PM2.5 Associated with Hepatocellular Steatosis.

Hepatic steatosis is the first step in a series of events that drives hepatic disease and has been considerably associated with exposure to fine particulate matter (PM2.5). Although the chemical constituents of particles matter in the negative health effects, the specific components of PM2.5 that trigger hepatic steatosis remain unclear. New strategies prioritizing the identification of the key components with the highest potential to cause adverse effects among the numerous components of PM2.5 are needed. Herein, we established a high-resolution mass spectrometry (MS) data set comprising the hydrophobic organic components corresponding to 67 PM2.5 samples in total from Taiyuan and Guangzhou, two representative cities in North and South China, respectively. The lipid accumulation bioeffect profiles of the above samples were also obtained. Considerable hepatocyte lipid accumulation was observed in most PM2.5 extracts. Subsequently, 40 of 695 components were initially screened through machine learning-assisted data filtering based on an integrated bioassay with MS data. Next, nine compounds were further selected as candidates contributing to hepatocellular steatosis based on absorption, distribution, metabolism, and excretion evaluation and molecular dockingin silico. Finally, seven components were confirmed in vitro. This study provided a multilevel screening strategy for key active components in PM2.5 and provided insight into the hydrophobic PM2.5 components that induce hepatocellular steatosis.

Higher temperature and humidity exacerbate pollutant-associated lung dysfunction in the elderly.

RATIONALE: Air pollution and extreme temperature and humidity are risk factors for lung dysfunction, but their interactions are not clearly understood. OBJECTIVES: To assess the impact of exposure to air pollutants and meteorological factors on lung function, and the contribution of their interaction to the overall effect. METHODS: The peak expiratory flow rates of 135 participants were repeatedly measured during up to four visits. Two weeks before each visit, the concentrations of gaseous pollutants and 19 fine particle components, and the temperature and relative humidity, were continuously monitored in the community where they lived. A Bayesian Kernel machine regression model was used to explore the non-linear exposure-response relationships of the peak expiratory flow rate with pollutant exposure and meteorological factors, and their interactions. MEASUREMENTS AND MAIN RESULTS: Increased temperature and relative humidity could exacerbate pollutant-associated decline in the peak expiratory flow rate, although their associations with lung dysfunction disappeared after adjustment for pollutant exposure. For example, declines of peak expiratory flow rate associated with interquartile range increase of 3-day cadmium exposure were -0.03 and -0.07 units, when temperature was at 0.1 and 19.5 °C, respectively. Decreased temperature were associated with declines of peak expiratory flow rate after adjustment for pollutant exposure, and had interaction with pollutant exposure on lung dysfunction. CONCLUSIONS: High temperature, low temperature, and high humidity were all high-risk factors for lung dysfunction, and their interactions with pollutant levels contributed greatly to the overall effects.

Ambient Air Pollution and Atherosclerosis: A Potential Mediating Role of Sphingolipids.

BACKGROUND: The pathophysiological mechanisms of air pollution-induced atherosclerosis are incompletely understood. Sphingolipids serve as biological intermediates during atherosclerosis development by facilitating production of proatherogenic apoB (apolipoprotein B)-containing lipoproteins. We explored whether sphingolipids mediate the proatherogenic effects of air pollution. METHODS: This was a prospective panel study of 110 participants (mean age 56.5 years) followed from 2013 to 2015 in Beijing, China. Targeted lipidomic analyses were used to quantify 24 sphingolipids in 579 plasma samples. The mass concentrations of ambient particulate matter ≤2.5 µm in diameter (PM2.5) were continuously monitored by a fixed station. We evaluated the associations between sphingolipid levels and average PM2.5 concentrations 1-30 days before clinic visits using linear mixed-effects models and explored whether sphingolipids mediate PM2.5-associated changes in the levels of proatherogenic apoB-containing lipoproteins (LDL-C [low-density lipoprotein cholesterol] and non-HDL-C [nonhigh-density lipoprotein cholesterol]) using mediation analyses. RESULTS: We observed significant increases in the levels of non-HDL-C and fourteen sphingolipids associated with PM2.5 exposure, from short- (14 days) to medium-term (30 days) exposure time windows. The associations exhibited near-monotonic increases and peaked in 30-day time window. Increased levels of the sphingolipids, namely, sphinganine, ceramide C24:0, sphingomyelins C16:0/C18:0/C18:1/C20:0/C22:0/C24:0, and hexosylceramides C16:0/C18:0/C20:0/C22:0/C24:0/C24:1 significantly mediated 32%, 58%, 35% to 93%, and 23% to 86%, respectively, of the positive association between 14-day PM2.5 average and the non-HDL-C level, but not the LDL-C level. Similar mediation effects (19%-91%) of the sphingolipids were also observed in 30-day time window. CONCLUSIONS: Our results suggest that sphingolipids may mediate the proatherogenic effects of short- and medium-term PM2.5 exposure.

Molecular Composition of Beijing PM2.5 Brown Carbon Revealed by an Untargeted Approach Based on Gas Chromatography and Time-of-Flight Mass Spectrometry.

The knowledge of the chemical composition of brown carbon (BrC) is limited to the categories of components or parts of specific organic components. In this paper, the light-absorbing properties and molecular compositions of lipid-soluble organic components in fine particulate matter of Beijing from 2016 to 2018, characterized by an ultraviolet-visible spectrometer and gas chromatography coupled with time-of-flight mass spectrometry, respectively, were combined to untargetedly screen the key BrC molecules by a partial least squares regression model for the first time. A total of 421 molecules were obtained, where 61 molecules were identified qualitatively and 22 molecules quantitatively. To the best of our knowledge, 11 molecules were newly identified BrC species. These qualitative molecules included polycyclic aromatic hydrocarbons with higher ambient concentrations and mass absorbing efficiencies (MAEs), as well as oxygen- and nitrogen-containing aromatic components with relatively lower concentrations and MAEs. The absorption contribution at 365 nm of quantified BrC species to lipid-soluble BrC during heating seasons was 39.1 ± 17.0%, which was about 5 times as high as previous studies. These results help establish a complete BrC molecular database and provide data support for better evaluating the climate effect of atmospheric carbonaceous aerosols and formulating air pollution control strategies.

A Systematic Review of Polycyclic Aromatic Hydrocarbon Derivatives: Occurrences, Levels, Biotransformation, Exposure Biomarkers, and Toxicity.

Polycyclic aromatic hydrocarbon (PAH) derivatives constitute a significant class of emerging contaminants that have been ubiquitously detected in diverse environmental matrixes, with some even exhibiting higher toxicities than their corresponding parent PAHs. To date, compared with parent PAHs, fewer systematic summaries and reanalyses are available for PAH derivatives with great environmental concerns. This review summarizes the current knowledge on the chemical species, levels, biotransformation patterns, chemical analytical methods, internal exposure routes with representative biomarkers, and toxicity of PAH derivatives, primarily focusing on nitrated PAHs (NPAHs), oxygenated PAHs (OPAHs), halogenated PAHs (XPAHs), and alkylated PAHs (APAHs). A collection of 188 compounds from four categories, 44 NPAHs, 36 OPAHs, 56 APAHs, and 52 XPAHs, has been compiled from 114 studies that documented the environmental presence of PAH derivatives. These compounds exhibited weighted average air concentrations that varied from a lower limit of 0.019 pg/m3 to a higher threshold of 4060 pg/m3. Different analytical methods utilizing comprehensive two-dimensional gas chromatography coupled with high-resolution time-of-flight mass spectrometry (GC × GC-TOF-MS), gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF-MS), comprehensive two-dimensional gas chromatography coupled to quadrupole mass spectrometry (GC × GC-QQQ-MS), and Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS), that adopted untargeted strategies for the identification of PAH derivatives are also reviewed here. Additionally, an in-depth analysis of biotransformation patterns for each category is provided, including the likelihood of specific biotransformation reaction types. For the toxicity, we primarily summarized key metabolic activation pathways, which could result in the formation of reactive metabolites capable of covalently bonding with DNA and tissue proteins, and potential health outcomes such as carcinogenicity and genotoxicity, oxidative stress, inflammation and immunotoxicity, and developmental toxicity that might be mediated by the aryl hydrocarbon receptor (AhR). Finally, we pinpoint research challenges and emphasize the need for further studies on identifying PAH derivatives, tracking external exposure levels, evaluating internal exposure levels and associated toxicity, clarifying exposure routes, and considering mixture exposure effects. This review aims to provide a broad understanding of PAH derivatives' identification, environmental occurrence, human exposure, biotransformation, and toxicity, offering a valuable reference for guiding future research in this underexplored area.

Polar Nitrated Aromatic Compounds in Urban Fine Particulate Matter: A Focus on Formation via an Aqueous-Phase Radical Mechanism.

Polar nitrated aromatic compounds (pNACs) are key ambient brown carbon chromophores; however, their formation mechanisms, especially in the aqueous phase, remain unclear. We developed an advanced technique for pNACs and measured 1764 compounds in atmospheric fine particulate matter sampled in urban Beijing, China. Molecular formulas were derived for 433 compounds, of which 17 were confirmed using reference standards. Potential novel species with up to four aromatic rings and a maximum of five functional groups were found. Higher concentrations were detected in the heating season, with a median of 82.6 ng m-3 for Σ17pNACs. Non-negative matrix factorization analysis indicated that primary emissions particularly coal combustion were dominant in the heating season. While in the non-heating season, aqueous-phase nitration could generate abundant pNACs with the carboxyl group, which was confirmed by their significant association with the aerosol liquid water content. Aqueous-phase formation of 3- and 5-nitrosalicylic acids instead of their isomer of 4-hydroxy-3-nitrobenzoic acid suggests the existence of an intermediate where the intramolecular hydrogen bond favors kinetics-controlled NO2• nitration. This study provides not only a promising technique for the pNAC measurement but also evidence for their atmospheric aqueous-phase formation, facilitating further evaluation of pNACs' climatic effects.

Insights into the Peroxide-Bicyclic Intermediate Pathway of Aromatic Photooxidation: Experimental Yields and NOx-Dependency of Ring-Opening and Ring-Retaining Products.

Aromatic hydrocarbons are important contributors to the formation of ozone and secondary organic aerosols in urban environments. The different parallel pathways in aromatic oxidation, however, remain inadequately understood. Here, we investigated the production yields and chemical distributions of gas-phase tracer products during the photooxidation of alkylbenzenes at atmospheric OH levels with NOx present using high-resolution mass spectrometers. The peroxide-bicyclic intermediate pathway emerged as the major pathway in aromatic oxidation, accounting for 52.1 ± 12.6%, 66.1 ± 16.6%, and 81.4 ± 24.3% of the total OH oxidation of toluene, m-xylene, and 1,3,5-trimethylbenzene, respectively. Notably, the yields of bicyclic nitrates produced from the reactions of bicyclic peroxy radicals (BPRs) with NO were considerably lower (3-5 times) than what the current mechanism predicted. Alongside traditional ring-opening products formed through the bicyclic pathway (dicarbonyls and furanones), we identified a significant proportion of carbonyl olefinic acids generated via the 1,5-aldehydic H-shift occurring in subsequent reactions of BPRs + NO, contributing 4-7% of the carbon flow in aromatic oxidation. Moreover, the observed NOx-dependencies of ring-opening and ring-retaining product yields provide insights into the competitive nature of reactions involving BPRs with NO, HO2, and RO2, which determine the refined product distributions and offer an explanation for the discrepancies between the experimental and model-based results.

Development and validation of a simple and rapid HILIC-MS/MS method for the quantification of low-abundant lysoglycerophospholipids in human plasma.

Lysoglycerophospholipids (Lyso-GPLs) are an essential class of signaling lipids with potential roles in human diseases, such as cancer, central nervous system diseases, and atherosclerosis. Current methods for the quantification of Lyso-GPLs involve complex sample pretreatment, long analysis times, and insufficient validation, which hinder the research of Lyso-GPLs in human studies, especially for Lyso-GPLs with low abundance in human plasma such as lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylglycerol (LPG), lysophosphatidylserine (LysoPS), lyso-platelet-activating factor (LysoPAF), and cyclic phosphatidic acid (cPA). Herein, we report the development and validation of a simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of Lyso-GPLs with low abundance in plasma. Protein precipitation using MeOH for Lyso-GPL extraction, quick separation (within 18 min) based on hydrophilic interaction liquid chromatography (HILIC), and sensitive MS detection under dynamic multiple reaction monitoring (dMRM) mode enabled efficient quantification of 22 Lyso-GPLs including 2 cPA, 4 LPG, 11 LPA, 2 LysoPS, and 3 LysoPAF in 50 µL of human plasma. The present method showed good linearity (goodness of fit, 0.99823-0.99995), sensitivity (lower limit of quantification, 0.03-14.06 ng/mL), accuracy (73-117%), precision (coefficient of variation ≤ 28%), carryover (≤ 17%), recovery (80-110%), and stability (83-123%). We applied the method in an epidemiological study and report concentrations of 18 Lyso-GPLs in 567 human plasma samples comparable to those of previous studies. Significant negative associations of LysoPAF C18, LysoPAF C18:1, and LysoPAF C16 with homeostatic model assessment for insulin resistance (HOMA-IR) level were observed; this indicates possible roles of LysoPAF in glucose homeostasis. The application of the present method will improve understanding of the roles of circulating low-abundant Lyso-GPLs in health and diseases.

Photocatalytic Role of Atmospheric Soot Particles under Visible-Light Irradiation: Reactive Oxygen Species Generation, Self-Oxidation Process, and Induced Higher Oxidative Potential and Cytotoxicity.

It is known that there are semiconductor oxides involved in mineral dust, which have photocatalytic properties. However, soot particles contained in carbonaceous aerosol and their photoactivity under sunlight are rarely realized. In this study, reactive oxygen species (ROS) such as superoxide anions and hydroxyl radicals were generated upon visible-light irradiation of soot particles, and the production activity was consistent with the carbonaceous core content, indicating that the atmospheric soot particles can serve as a potential photocatalyst. The increase of oxygen-containing functional groups, environmentally persistent free radicals, oxygenated polycyclic aromatic hydrocarbons, and the oxidative potential (OP) of soot after irradiation confirmed the occurrence of visible-light-triggered photocatalytic oxidation of the soot itself. The mechanism analyses suggested that the carbonaceous core caused the production of ROS, which subsequently oxidize the extractable organic species on the soot surface. It is oxidized organic extracts that are responsible for the enhancements of the OP, cell mortality, and intracellular ROS generation. These new findings shed light on both the photocatalytic role of the soot and the importance of ROS during the photochemical self-oxidation of soot triggered by visible light and will promote a more comprehensive understanding of both the atmospheric chemical behavior and health effects of soot particles.

A simple and rapid method for extraction and measurement of circulating sphingolipids using LC-MS/MS: a targeted lipidomic analysis.

Sphingolipids are a class of lipids with high structural diversity and biological pleiotropy. Mounting evidence supports a role for sphingolipids in regulating pathophysiology of cardiometabolic diseases, and they have been proposed as potential cardiometabolic biomarkers. Current methods for quantifying sphingolipids require laborious pretreatment and relatively large sample volumes, and cover limited species, hindering their application in epidemiological studies. Herein, we applied a time-, labor-, and sample-saving protocol simply using methanol for plasma sphingolipid extraction. It was compared with classical liquid-liquid extraction methods and showed significant advantages in terms of simplicity, sphingolipid coverage, and sample volume. By coupling the protocol with liquid chromatography using a wide-span mobile phase polarity parameter and tandem mass spectrometry operated in dynamic multiple reaction monitoring mode, 37 sphingolipids from 8 classes (sphingoid base, sphingoid base phosphate, ceramide-1-phosphate, lactosylceramide, hexosylceramide, sphingomyelin, ceramide, and dihydroceramide) were quantified within 16 min, using only 10 µL of human plasma. The current method showed good performance in terms of linearity (R2 > 0.99), intra- and interbatch accuracy (70-123%) and precision (RSD < 12%), matrix effect (91-121%), recovery (96-101%), analyte chemical stability (deviation < 19%), and carryover (< 16%). We successfully applied this method to quantify 33 detectable sphingolipids from 579 plasma samples of an epidemiological study within 10 days. The quantified sphingolipid concentrations were comparable with previous studies. Positive associations of ceramide C22:0/C24:0 and their precursors with homeostasis model assessment of insulin resistance suggested that the synthesis of the ceramides might be involved in insulin resistance. This novel method constitutes a simple and rapid approach to quantify circulating sphingolipids for epidemiological studies using targeted lipidomic analysis, which will help elucidate the sphingolipid-regulated pathways underlying cardiometabolic diseases.

Arachidonic acid metabolism and inflammatory biomarkers associated with exposure to polycyclic aromatic hydrocarbons.

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with systemic inflammation, yet what mechanisms regulate PAHs' inflammatory effects are less understood. This study evaluated the change of arachidonic acid (ARA) metabolites and inflammatory biomarkers in response to increased exposure to PAHs among 26 non-smoking healthy travelers from Los Angeles to Beijing. Traveling from Los Angeles to Beijing significantly increased urinary metabolites of dibenzofuran (800%), fluorene (568%), phenanthrene (277%), and pyrene (176%), accompanied with increased C-reactive protein, fibrinogen, IL-8, and IL-10, and decreased MCP-1, sCD40L, and sCD62P levels in the blood. Meanwhile, the travel increased the levels of ARA lipoxygenase metabolites that were positively associated with a panel of pro-inflammatory biomarkers. Concentrations of cytochrome P450 metabolite were also increased in Beijing and were negatively associated with sCD62P levels. In contrast, concentrations of ARA cyclooxygenase metabolites were decreased in Beijing and were negatively associated with anti-inflammatory IL-10 levels. Changes in both inflammatory biomarkers and ARA metabolites were reversed 4-7 weeks after participants returned to Los Angeles and were associated with urinary PAH metabolites, but not with other exposures such as secondhand smoke, stress, or diet. These results suggested possible roles of ARA metabolic alteration in PAHs-associated inflammatory effects.

Pro-thrombotic changes associated with exposure to ambient ultrafine particles in patients with chronic obstructive pulmonary disease: roles of lipid peroxidation and systemic inflammation.

BACKGROUND: Exposure to particulate matter air pollution is associated with an increased risk of cardiovascular mortality in patients with chronic obstructive pulmonary disease (COPD), but the underlying mechanisms are not yet understood. Enhanced platelet and pro-thrombotic activity in COPD patients may explain their increased cardiovascular risk. We aim to explore whether short-term exposure to ambient particulate matter is associated with pro-thrombotic changes in adults with and without COPD, and investigate the underlying biological mechanisms in a longitudinal panel study. Serum concentration of thromboxane (Tx)B2 was measured to reflect platelet and pro-thrombotic activity. Lipoxygenase-mediated lipid peroxidation products (hydroxyeicosatetraenoic acids [HETEs]) and inflammatory biomarkers (interleukins [ILs], monocyte chemoattractant protein-1 [MCP-1], tumour necrosis factor alpha [TNF-α], and macrophage inflammatory proteins [MIPs]) were measured as potential mediating determinants of particle-associated pro-thrombotic changes. RESULTS: 53 COPD and 82 non-COPD individuals were followed-up on a maximum of four visits conducted from August 2016 to September 2017 in Beijing, China. Compared to non-COPD individuals, the association between exposure to ambient ultrafine particles (UFPs) during the 3-8 days preceding clinical visits and the TxB2 serum concentration was significantly stronger in COPD patients. For example, a 103/cm3 increase in the 6-day average UFP level was associated with a 25.4% increase in the TxB2 level in the COPD group but only an 11.2% increase in the non-COPD group. The association in the COPD group remained robust after adjustment for the levels of fine particulate matter and gaseous pollutants. Compared to the non-COPD group, the COPD group also showed greater increases in the serum concentrations of 12-HETE (16.6% vs. 6.5%) and 15-HETE (9.3% vs. 4.5%) per 103/cm3 increase in the 6-day UFP average. The two lipid peroxidation products mediated 35% and 33% of the UFP-associated increase in the TxB2 level of COPD patients. UFP exposure was also associated with the increased levels of IL-8, MCP-1, MIP-1α, MIP-1ß, TNF-α, and IL-1ß in COPD patients, but these inflammatory biomarkers did not mediate the TxB2 increase. CONCLUSIONS: Short-term exposure to ambient UFPs was associated with a greater pro-thrombotic change among patients with COPD, at least partially driven by lipoxygenase-mediated pathways following exposure. Trial registration ChiCTR1900023692 . Date of registration June 7, 2019, i.e. retrospectively registered.

Organic Iodine Compounds in Fine Particulate Matter from a Continental Urban Region: Insights into Secondary Formation in the Atmosphere.

Atmospheric iodine chemistry can significantly affect the atmospheric oxidation capacity in certain regions. In such processes, particle-phase organic iodine compounds (OICs) are key reservoir species in their loss processes. However, their presence and formation mechanism remain unclear, especially in continental regions. Using gas chromatography and time-of-flight mass spectrometry coupled with both electron capture negative ionization and electron impact sources, this study systematically identified unknown OICs in 2-year samples of ambient fine particulate matter (PM2.5) collected in Beijing, an inland city. We determined the molecular structure of 37 unknown OICs, among which six species were confirmed by reference standards. The higher concentrations for ∑37OICs (median: 280 pg m-3; range: 49.0-770 pg m-3) measured in the heating season indicate intensive coal combustion sources of atmospheric iodine. 1-Iodo-2-naphthol and 4-iodoresorcinol are the most abundant species mainly from primary combustion emission and secondary formation, respectively. The detection of 2- and 4-iodoresorcinols, but not of iodine-substituted catechol/hydroquinone or 5-iodoresorcinol, suggests that they are formed via the electrophilic substitution of resorcinol by hypoiodous acid, a product of the reaction of iodine with ozone. This study reports isomeric information on OICs in continental urban PM2.5 and provides valuable evidence on the formation mechanism of OICs in ambient particles.

Metabolomic Changes after Subacute Exposure to Polycyclic Aromatic Hydrocarbons: A Natural Experiment among Healthy Travelers from Los Angeles to Beijing.

Emerging epidemiological evidence has associated exposure to polycyclic aromatic hydrocarbons (PAHs) with chronic diseases including cardiometabolic diseases and neurodegeneration. However, little information is available about their subacute effects, which may accumulate over years and contribute to chronic disease development. To fill this knowledge gap, we designed a natural experiment among 26 healthy young adults who were exposed to elevated PAHs for 10 weeks after traveling from Los Angeles to Beijing in 2014 and 2015. Serum was collected before, during, and after the trip for metabolomics analysis. We identified 50 metabolites that significantly changed 6-8 weeks after the travel to Beijing (FDR < 5%). The network analysis revealed two main independent modules. Module 1 was allocated to oxidative homeostasis-related response and module 2 to delayed enzymatic deinduction response. Remarkably, the module 1 metabolites were recovered 4-7 weeks after participants' return, while the module 2 metabolites were not. Urinary hydroxylated PAHs were significantly associated with metabolites from both modules, while PAH carboxylic acids, likely metabolites of alkylated PAHs, were only associated with antioxidation-related metabolites. These results suggested differential subacute effects of unsubstituted and alkylated PAHs. Further studies are warranted to elucidate the role of the reversibility of metabolite changes in adverse health effects of PAHs.

Organic Components of Personal PM2.5 Exposure Associated with Inflammation: Evidence from an Untargeted Exposomic Approach.

Fine particulate matter (PM2.5) can promote chronic diseases through the fundamental mechanism of inflammation; however, systemic information is lacking on the inflammatory PM2.5 components. To decipher organic components from personal PM2.5 exposure that were associated with respiratory and circulatory inflammatory responses in older adults, we developed an exposomic approach using trace amounts of particles and applied it on 424 personal PM2.5 samples collected in a panel study in Beijing. Applying an integrated multivariate and univariate untargeted strategy, a total of 267 organic compounds were filtered and then chemically identified according to their association with exhaled nitric oxide (eNO)/interleukin (IL)-6 or serum IL-1ß/IL-6, with monocyclic and polycyclic aromatic compounds (i.e., MACs and PACs) as the representatives. Indoor-derived species with medium volatility including MACs were mainly associated with systemic inflammation, while low-volatile ambient components that originate from combustion sources, such as PACs, were mostly associated with airway inflammation. Following ambient component exposure, we found an inverted U-shaped relationship on change of eNO with insulin resistance, suggesting a higher risk of cardiopulmonary dysfunction for individuals with homeostatic model assessment for insulin resistance (HOMA-IR) levels > 2.3. Overall, this study provided a practical untargeted strategy for the systemic investigation of PM2.5 components and proposed source-specific inflammatory effects.

Secondary Production of Gaseous Nitrated Phenols in Polluted Urban Environments.

Nitrated phenols (NPs) are important atmospheric pollutants that affect air quality, radiation, and health. The recent development of the time-of-flight chemical ionization mass spectrometer (ToF-CIMS) allows quantitative online measurements of NPs for a better understanding of their sources and environmental impacts. Herein, we deployed nitrate ions as reagent ions in the ToF-CIMS and quantified six classes of gaseous NPs in Beijing. The concentrations of NPs are in the range of 1 to 520 ng m-3. Nitrophenol (NPh) has the greatest mean concentration. Dinitrophenol (DNP) shows the greatest haze-to-clean concentration ratio, which may be associated with aqueous production. The high concentrations and distinct diurnal profiles of NPs indicate a strong secondary formation to overweigh losses, driven by high emissions of precursors, strong oxidative capacity, and high NOx levels. The budget analysis on the basis of our measurements and box-model calculations suggest a minor role of the photolysis of NPs (<1 ppb h-1) in producing OH radicals. NPs therefore cannot explain the underestimated OH production in urban environments. Discrepancies between these results and the laboratory measurements of the NP photolysis rates indicate the need for further studies aimed at understanding the production and losses of NPs in polluted urban environments.

Precursors and Pathways Leading to Enhanced Secondary Organic Aerosol Formation during Severe Haze Episodes.

Molecular analyses help to investigate the key precursors and chemical processes of secondary organic aerosol (SOA) formation. We obtained the sources and molecular compositions of organic aerosol in PM2.5 in winter in Beijing by online and offline mass spectrometer measurements. Photochemical and aqueous processing were both involved in producing SOA during the haze events. Aromatics, isoprene, long-chain alkanes or alkenes, and carbonyls such as glyoxal and methylglyoxal were all important precursors. The enhanced SOA formation during the severe haze event was predominantly contributed by aqueous processing that was promoted by elevated amounts of aerosol water for which multifunctional organic nitrates contributed the most followed by organic compounds having four oxygen atoms in their formulae. The latter included dicarboxylic acids and various oxidation products from isoprene and aromatics as well as products or oligomers from methylglyoxal aqueous uptake. Nitrated phenols, organosulfates, and methanesulfonic acid were also important SOA products but their contributions to the elevated SOA mass during the severe haze event were minor. Our results highlight the importance of reducing nitrogen oxides and nitrate for future SOA control. Additionally, the formation of highly oxygenated long-chain molecules with a low degree of unsaturation in polluted urban environments requires further research.

Pro-Oxidative and Proinflammatory Effects After Traveling From Los Angeles to Beijing: A Biomarker-Based Natural Experiment.

BACKGROUND: Exposure to air pollution increases cardiovascular morbidity and mortality. Preventing chronic cardiovascular diseases caused by air pollution relies on detecting the early effects of pollutants on the risk of cardiovascular disease development, which is limited by the lack of sensitive biomarkers. We have previously identified promising biomarkers in experimental animals but comparable evidence in humans is lacking. METHODS: Air pollution is substantially worse in Beijing than in Los Angeles. We collected urine and blood samples from 26 nonsmoking, healthy adult residents of Los Angeles (mean age, 23.8 years; 14 women) before, during, and after spending 10 weeks in Beijing during the summers of 2014 and 2015. We assessed a panel of circulating biomarkers indicative of lipid peroxidation and inflammation. Personal exposure to polycyclic aromatic hydrocarbons (PAHs), a group of combustion-originated air pollutants, was assessed by urinary PAH metabolite levels. RESULTS: Urinary concentrations of 4 PAH metabolites were 176% (95% CI, 103% to 276%) to 800% (95% CI, 509% to 1780%) greater in Beijing than in Los Angeles. Concentrations of 6 lipid peroxidation biomarkers were also increased in Beijing, among which 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid levels reached statistical significance (false discovery rate <5%), but not 8-isoprostane (20.8%; 95% CI, -5.0% to 53.6%). The antioxidative activities of paraoxonase (-9.8%; 95% CI, -14.0% to -5.3%) and arylesterase (-14.5%; 95% CI, -22.3% to -5.8%) were lower and proinflammatory C-reactive protein (101%; 95% CI, 3.3% to 291%) and fibrinogen (48.3%; 95% CI, 4.9% to 110%) concentrations were higher in Beijing. Changes in all these biomarkers were reversed, at least partially, after study participants returned to Los Angeles. Changes in most outcomes were associated with urinary PAH metabolites (P<0.05). CONCLUSIONS: Traveling from a less-polluted to a more-polluted city induces systemic pro-oxidative and proinflammatory effects. Changes in the levels of 5-, 12-, and 15-hydroxyeicosatetraenoic acid and 9- and 13-hydroxyoctadecadienoic acid as well as paraoxonase and arylesterase activities in the blood, in association with exposures to PAH metabolites, might have important implications in preventive medicine as indicators of increased cardiovascular risk caused by air pollution exposure.

Particulate Matter Toxicity Is Nrf2 and Mitochondria Dependent: The Roles of Metals and Polycyclic Aromatic Hydrocarbons.

Particulate matter (PM), an important component of air pollution, induces significant adverse health effects. Many of the observed health effects caused by inhaled PM are associated with oxidative stress and inflammation. This association has been linked in particular to the particles' chemical components, especially the inorganic/metal and the organic/polycyclic aromatic hydrocarbon (PAH) fractions, and their ability to generate reactive oxygen species in biological systems. The transcription factor NF-E2 nuclear factor erythroid-related factor 2 (Nrf2) is activated by redox imbalance and regulates the expression of phase II detoxifying enzymes. Nrf2 plays a key role in preventing PM-induced toxicity by protecting against oxidative damage and inflammation. This review focuses on specific PM fractions, particularly the dissolved metals and PAH fractions, and their roles in inducing oxidative stress and inflammation in cell and animal models with respect to Nrf2 and mitochondria.