Fine particulate matter exposure and systemic inflammation: A potential mediating role of bioactive lipids.

Inflammation is a key mechanism underlying the adverse health effects of exposure to fine particulate matter (PM2.5). Bioactive lipids in the arachidonic acid (ARA) pathway are important in the regulation of inflammation and are reportedly altered by PM2.5 exposure. Ceramide-1-phosphate (C1P), a class of sphingolipids, is required to initiate ARA metabolism. We examined the role of C1P in the alteration of ARA metabolism after PM2.5 exposure and explored whether changes in the ARA pathway promoted systemic inflammation based on a panel study involving 112 older adults in Beijing, China. Ambient PM2.5 levels were continuously monitored at a fixed station from 2013 to 2015. Serum cytokine levels were measured to assess systemic inflammation. Multiple bioactive lipids in the ARA pathway and three subtypes of C1P were quantified in blood samples. Mediation analyses were performed to test the hypotheses. We observed that PM2.5 exposure was positively associated with inflammatory cytokines and the three subtypes of C1P. Mediation analyses showed that C1P significantly mediated the associations of ARA and 5, 6-dihydroxyeicosatrienoic acid (5, 6-DHET), an ARA metabolite, with PM2.5 exposure. ARA, 5, 6-DHET, and leukotriene B4 mediated systemic inflammatory response to PM2.5 exposure. For example, C1P C16:0 (a subtype of C1P) mediated a 12.9 % (95 % confidence interval: 3.7 %, 32.5 %) increase in ARA associated with 3-day moving average PM2.5 exposure, and ARA mediated a 27.1 % (7.8 %, 61.2 %) change in interleukin-8 associated with 7-day moving average PM2.5 exposure. Our study indicates that bioactive lipids in the ARA and sphingolipid metabolic pathways may mediate systemic inflammation after PM2.5 exposure.

Exercise intervention in middle-aged and elderly individuals with insomnia improves sleep and restores connectivity in the motor network.

Exercise is a potential treatment to improve sleep quality in middle-aged and elderly individuals. Understanding exercise-induced changes in functional plasticity of brain circuits that underlie improvements in sleep among middle-aged and older adults can inform treatment of sleep problems. The aim of the study is to identify the effects of a 12-week exercise program on sleep quality and brain functional connectivity in middle-aged and older adults with insomnia. The trial was registered with Chinese Clinical Trial Register (ChiCTR2000033652). We recruited 84 healthy sleepers and 85 individuals with insomnia. Participants with insomnia were assigned to receive either a 12-week exercise intervention or were placed in a 12-week waitlist control condition. Thirty-seven middle-aged and older adults in the exercise group and 30 in the waitlist group completed both baseline and week 12 assessments. We found that middle-aged and older adults with insomnia showed significantly worse sleep quality than healthy sleepers. At the brain circuit level, insomnia patients showed decreased connectivity in the widespread motor network. After exercise intervention, self-reported sleep was increased in the exercise group (P < 0.001) compared to that in the waitlist group. We also found increased functional connectivity of the motor network with the cerebellum in the exercise group (P < 0.001). Moreover, we observed significant correlations between improvement in subjective sleep indices and connectivity changes within the motor network. We highlight exercise-induced improvement in sleep quality and functional plasticity of the aging brain.

Particulate Air Pollution and Blood Pressure: Signaling by the Arachidonate Metabolism.

BACKGROUND: Short-term exposure to ambient particulate matter (PM) can raise blood pressure, but the underlying mechanisms are unclear. We explored whether arachidonate metabolites serve as biological intermediates in PM-associated prohypertensive changes. METHODS: This panel study recruited 110 adults aged 50 to 65 years living in Beijing, China. The participants' blood pressure, arterial stiffness, and cardiac and endothelial function were measured up to 7 times. The serum concentrations of arachidonate metabolites were quantified by targeted lipidomics. Ambient concentrations of fine PM (PM2.5), black carbon, and accumulation mode particles were continuously monitored at a station and their associations with the health indicators were evaluated. RESULTS: Interquartile range increases in 25 to 96-hour-lag exposure to PM2.5, black carbon, and accumulation mode particles were associated with significant increases in systolic blood pressure (brachial: 0.8-3.2 mm Hg; central: 0.7-2.8 mm Hg) and diastolic blood pressure (brachial, 0.5-1.5 mm Hg; central, 0.5-1.6 mm Hg). At least 1 pollutant was associated with increases in augmentation pressure and heart rate and decreases in reactive hyperemia index and ejection time. The serum concentrations of arachidonate were significantly increased by 3.3% to 14.6% in association with PM exposure, which mediated 9% of the PM-associated increases in blood pressure. The levels of eicosanoids from the cytochrome P450, cyclooxygenase, and lipoxygenase pathways changed with PM exposure, and those from the cytochrome pathway significantly mediated the association between PM exposure and blood pressure. CONCLUSIONS: Short-term exposure to particulate air pollution was associated with a prohypertensive change in adults, which was in part mediated by alteration of arachidonate metabolism.

Cardiovascular effects of wearing respirators against particulate matter: A randomized crossover trial.

Fine particles (PM2.5) are implicated as an important risk to cardiovascular health. N95 respirators had been widely used to provide protection by filtering particles. Yet the practical effects of wearing respirators have not been fully understood. This study aimed to evaluate the cardiovascular effects of respirator wearing against PM2.5 and underpin the understanding of the mechanisms of cardiovascular responses triggered by PM2.5. We conducted a randomized, double-blind crossover trial among 52 healthy adults in Beijing, China. Participants were exposed to outdoor PM2.5 for 2 h in alterations wearing true respirators (with membranes) or sham ones (without membranes). We measured ambient PM2.5 and tested the filtration efficiency of the respirators. We compared the heart rate variability (HRV), blood pressure and arterial stiffness indicators between the true respirator group and the sham respirator group. Concentrations of ambient PM2.5 during the 2-h exposure ranged from 4.9 to 255.0 µg/m3. The filtration efficiency of true respirators was 90.1 % and that of sham ones was 18.7 %. Between-group differences varied by pollution levels. On less polluted days (PM2.5< 75 µg/m3), participants wearing true respirators showed lower levels of HRV and higher levels of heart rate compared with those wearing sham respirators. These between-group differences were inconspicuous on heavily polluted days (PM2.5≥ 75 µg/m3). We found that a 10 µg/m3 increase in PM2.5 was associated with a 2.2 % to 6.4 % decrease in HRV, prominent at 1 h after the start of exposure. N95 respirators have good performance in reducing PM2.5 exposure. Short-term exposure to PM2.5 can induce very acute responses in autonomic nervous function. However, the overall effects of wearing respirators might be not always favorable to human health in terms of their inherent adverse effects, which seem dependent on the levels of air pollution. Precise individual protection recommendations warrant to be developed.

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.

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.

Personal exposure to electrophilic compounds of fine particulate matter and the inflammatory response: The role of atmospheric transformation.

Atmospheric oxidation can produce electrophilic compounds, altering the health effects induced by fine particulate matter (PM2.5); however, little is known about these electrophilic compounds or their health effects. Using electron capture negative ionization, we systematically detected 301 electrophilic compounds from personal PM2.5 samples in a panel study in urban Beijing. Most were oxygen-containing compounds with 3-17 double bond equivalents (DBE), suggesting the dominance of oxidized aromatic structures. Over 64% of the species, mostly outdoor-originated, were associated with inflammatory cytokines in both exhaled breath condensate and serum. Primary components of polycyclic aromatic hydrocarbons (PAHs) and high-DBE oxygenated PAHs, mainly from fossil fuel combustion, were positively associated with interleukin (IL)- 6, a cytokine related to oxidative homeostasis. Oxidized secondary species, particularly maleic and phthalic anhydrides, were negatively associated with IL-2/IL-8, which changed by - 3.8% to - 16.4% per one-fold increase in the abundance of the secondary source, indicating the immune disorders in response to the oxidized aerosols. Mediation analysis demonstrated the necessity of transformation products between atmospheric oxidation capacity and IL-2/IL-8 inhibition. This study provides new information on particulate electrophilic compounds and highlights the role of atmospheric chemistry in specific immune disorders.

Glucose Metabolic Disorders Enhance Vascular Dysfunction Triggered by Particulate Air Pollution: a Panel Study.

BACKGROUND: Vascular dysfunction is a biological pathway whereby particulate matter (PM) exerts deleterious cardiovascular effects. The effects of ambient PM on vascular function in prediabetic individuals are unclear. METHODS: A panel study recruited 112 Beijing residents with and without prediabetes. Multiple vascular function indices were measured up to 7 times. The associations between vascular function indices and short-term exposure to ambient PM, including fine particulate matter (PM2.5), ultrafine particles, accumulation mode particles, and black carbon, and the modification of these associations by glucose metabolic status were examined using linear mixed-effects models. RESULTS: Increases in brachial artery pulse pressure, central aortic pulse pressure, and ejection duration, and decreases in subendocardial viability ratio and reactive hyperemia index were significantly associated with at least one PM pollutant in all participants, indicating increased vascular dysfunction. For example, for an interquartile range increment in 5-day moving average ultrafine particles, brachial artery pulse pressure, and central aortic pulse pressure increased 5.4% (0.8%-10.4%) and 6.2% (1.2%-11.5%), respectively. Additionally, PM-associated changes in vascular function differed according to glucose metabolic status. Among participants with high fasting blood glucose levels (≥6.1 mmol/L), PM exposure was significantly associated with increased brachial artery systolic blood pressure, central aortic systolic blood pressure, brachial artery pulse pressure, central aortic pulse pressure, and augmentation pressure normalized to a heart rate of 75 bpm and decreased subendocardial viability ratio and reactive hyperemia index. Weaker or null associations were observed in the low-fasting blood glucose group. CONCLUSIONS: Glucose metabolic disorders may exacerbate vascular dysfunction associated with short-term ambient PM exposure.

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.

Fine particulate matter and vasoactive 20-hydroxyeicosatetraenoic acid: Insights into the mechanisms of the prohypertensive effects of particulate air pollution.

BACKGROUND: Emerging evidence suggests that biological intermediates play an important role in initiating fine particulate matter (PM2.5)-associated prohypertensive pathways, but sensitive biomarkers for this pathway are lacking. AIM: To explore whether short-term exposure to PM2.5 is associated with the concentration of 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoactive lipid relevant to the pathophysiology of hypertension. METHODS: In this longitudinal panel study, we repeatedly (up to seven times) measured the blood concentrations of 20-HETE in 120 adults living in Beijing, China. Ambient exposure metrics included the concentrations of hourly PM2.5 mass and daily PM2.5 constituents, including three carbonaceous components, eight water-soluble ions, and 16 trace elements. Linear mixed-effects models were used to examine the associations between the change in the 20-HETE concentration and short-term exposure to ambient PM2.5 metrics after adjustment for age, sex, body mass index, behavioral exposure, socioeconomic characteristics, and meteorological factors. RESULTS: The interquartile range (IQR) increase in the 7-15-hour-lag exposure to PM2.5 (80 µg/m3) was associated significantly with a 5.3% (95% confidence interval [CI], 0.1-10.7%) to 6.5% (95% CI, 1.7-11.6%) increase in the blood concentration of 20-HETE. The magnitude of the association differed by age, sex, prediabetic status, obesity, and hypertensive status, with a significantly greater increase in 20-HETE observed among those with fasting plasma glucose concentrations ≥ 6.1 mmol/L. In addition to the PM2.5 mass, the 20-HETE concentration was associated consistently with IQR increases in the 1-day lag exposure to organic carbon (5.7%), black carbon (9.5%), nitrate (3.9%), chloride (2.9%), copper (5.5%), zinc (4.7%), barium (4.1%), and lead (6.2%). The organic carbon estimate was robust in the two-pollutant models. Furthermore, increased 20-HETE correlated with elevated blood pressure (BP), although no mediation of 20-HETE on PM2.5-associated BP change was found. CONCLUSIONS: The 20-HETE blood concentration increased significantly in response to short-term exposure to ambient PM2.5, which may be partly responsible for the prohypertensive effects of PM2.5.

Serum branched-chain amino acids modifies the associations between air pollutants and insulin resistance.

Growing evidence supports that air pollution exposure has become a risk factor of type II diabetes mellitus through the induction of insulin resistance (IR), but the presented findings did not provide a consistent relationship between air pollution exposure and IR in the temporal scale and the magnitude. Reported associated with IR and air pollution exposure, branched-chain amino acids (BCAAs) in blood might modify the association between air pollution exposure and IR. We took advantage of an existing panel study on elderly people who were healthy or with pre-diabetes. Amino acids were analyzed from the serum samples using a UPLC-QQQ-MS, and the homeostasis model assessment of insulin resistance (HOMA-IR) values were calculated to represent the levels of IR in each visit. Exposures to PM2.5, NO2, SO2, CO, O3, and black carbon (BC) were estimated using data from a monitoring station. Linear mixed-effects models were applied to estimate the associations between the air pollution and HOMA-IR, as well as the modifying effects of BCAAs. We found significantly higher concentrations of BCAAs in the pre-diabetic subjects than healthy ones. The concentrations of BCAAs were all significantly associated with HOMA-IR. For subjects with high-level BCAAs, HOMA-IR was positively associated with an IQR increase in PM2.5, NO2, BC, and CO at lag day 2 and in PM2.5, SO2, NO2, BC, and CO at lag day 7. While for subjects with low-level BCAAs, there was no significant association observed at any lag day except for CO at lag day 5. The study provided evidence that circulating BCAAs may modify the relationship between air pollution exposure and the level of insulin resistance in humans.

Proinflammatory lipid signals trigger the health effects of air pollution in individuals with prediabetes.

Individuals with metabolic disorders exhibit enhanced susceptibility to the cardiovascular health effects of particulate air pollution, but the underlying mechanisms are not yet understood. We aim to assess whether changes in proinflammatory lipid signals are associated with fine particulate matter (PM2.5) exposure in individuals with and without prediabetes. A longitudinal panel study was conducted in Beijing, China, and included 120 participants followed up over 589 clinical visits from August 2013 to February 2015. We measured 12 lipids derived from arachidonic acid pathways in blood samples of the participants via targeted lipidomic analyses. Ambient PM2.5 concentrations were continuously monitored at a station for associations with the lipids. Among the 120 participants, 110 (mean [SD] age at recruitment, 56.5 [4.2] years; 31 prediabetics) who visited the clinic at least twice over the follow-up period were assigned exposure values of the outdoor residential PM2.5 concentrations during the 1-14 days preceding each clinical visit. With an interquartile range increase in the 1-day-lag PM2.5 exposure (64.0 µg/m3), the prediabetic group had consistently greater increases in the concentration of arachidonate metabolites derived from the cytochrome P450 (CYP450) pathway (5,6-DHET, 15.8% [95% CI, 3.5-29.7%]; 8,9-DHET, 9.7% [95% CI, 0.6-19.6%]; 11,12-DHET, 8.3% [95% CI, 1.9-15.1%]; 14,15-DHET, 7.4% [95% CI, 0.9-14.4%]; and 20-HETE, 8.9% [95% CI, 1.0-17.5%]), compared with the healthy group. Among CYP450-derived lipids, 14,15-DHET and 20-HETE significantly mediated 8% and 8% of the PM2.5-associated increase in white blood cells, 10% and 13% of that in neutrophils, and 20% and 23% of that in monocytes, respectively, in the prediabetic group. In conclusion, proinflammatory lipid signals from CYP450 pathways triggered the health effects of particulate air pollution in individuals with prediabetes, suggesting that targeting lipid metabolism has therapeutic potential to attenuate or prevent the cardiovascular effects of air pollution in susceptible populations.

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.

The health effects of wearing facemasks on cardiopulmonary system of healthy young adults: A double-blinded, randomized crossover trial.

BACKGROUND: Facemask had increasingly been utilized as a personal protective measure to reduce exposure to ambient particulate matter (PM) during heavily-polluted days and routine life. However, evidence on the potential effects on cardiovascular system by wearing particulate-filtering facemask was limited. METHODS: We conducted a double-blinded randomized crossover trial (RCT) to evaluate the effects of wearing N95 facemasks on the molecular responses of cardiopulmonary system among 52 healthy college students in Beijing, China. We measured cardiopulmonary health indicators and collected biological samples before and after (up to 5 h at multiple time points) a 2-h walk to examine the changes in lung function, biomarkers of respiratory and systemic oxidative stress/inflammation. We applied linear mixed-effect models to evaluate the effect of the facemask-intervention on the health of cardio-pulmonary system. RESULTS: In the trial wearing real facemasks, FEV1 increased by 2.05% (95% CI: 0.27%-3.87%), 2.80% (95% CI: 1.00%-4.63%), and 2.87% (95% CI: 1.07%-4.70%) at V1 (30-min), V2 (3-h), and V3 (5-h) after the 2-h walk outsides, respectively. Compared with participants wearing the sham mask, the percentage change of nitrate in EBC was lower among those wearing the real mask. After the 2-h exposure, urinary MDA levels increased compared to the baseline in both trials. Real trial was lower than sham trial for 6 cytokines (i.e., IL-6, IL-10, IL-13, IL-17A, IFN-γ and TNF-α) in serum at 5-h post-exposure. Wearing facemasks on polluted days produced better improvement, however, on cleaner days, the improvement was weaker. CONCLUSIONS: Short-term use of N95 facemasks appeared to effectively reduce the levels of lung function declines, the respiratory oxidative stress, and the systemic inflammation/oxidative stress which may be induced by short-term exposure to PM. Wearing facemasks on polluted days (PM2.5 > 75 µg/m3) presented larger beneficial effects on the cardiopulmonary health than in clean days (PM2.5 < 75 µg/m3).

Changes in bioactive lipid mediators in response to short-term exposure to ambient air particulate matter: A targeted lipidomic analysis of oxylipin signaling pathways.

BACKGROUND: Exposure to ambient air particulate matter (PM) is a risk factor for cardiometabolic diseases. The knowledge of the underlying mechanisms is still evolving, but systemic inflammation and oxidative stress are central to the ability of PM to induce cardiometabolic effects. Oxylipins derived from polyunsaturated fatty acids (PUFAs) are bioactive lipid mediators that have fundamental roles in the signaling of inflammatory events. However, the associations between oxylipins and short-term exposure to PM in humans are unknown. METHODS: Using targeted lipidomic analyses, we measured 16 oxylipins derived from lipoxygenase (LOX), cytochrome P450 (CYP), and cyclooxygenase (COX) pathways and their parent PUFAs in serum samples of 110 adults enrolled in a panel study in Beijing, China. Each participant completed 2-7 clinical visits from 2013 to 2015. PM with aerodynamic diameter ≤ 2.5 µm (PM2.5) and ≤ 0.1 µm (ultrafine particles, UFPs) were continuously monitored at a station. Linear mixed-effects models were applied to examine the associations between changes in lipid mediators and exposure to ambient PM during the preceding 1 to 3 days before the clinical visit. RESULTS: Serum concentrations of PUFAs, including omega-6 arachidonic acid (ARA) and omega-3 eicosapentaenoic acid (EPA), were significantly increased in association with interquartile range (IQR) increases in PM with different exposure windows (i.e., 1-3 days). Regarding oxylipins, significant PM-associated changes included increases in LOX-derived leukotriene B4 (LTB4), 12(S)-, 15(S)-hydroxyeicosatetraenoic acid (HETE), 12-hydroxyeicosapentaenoic acid (HEPE), and 17-hydroxydocosahexaenoic acid (HDHA); an increase in CYP-derived 5,6-dihydroxyeicosatrienoic acid (DHET); and a decrease in COX-derived prostaglandin E2. CONCLUSIONS: Short-term exposure to PM was associated with PUFAs and oxylipins derived from LOX, CYP, and COX pathways in humans. Our findings provide mechanistic insight suggesting bioactive oxylipins might be used as biomarkers and have important implications as mediators of PM-associated systemic cardiometabolic effects.

Associations between changes in adipokines and exposure to fine and ultrafine particulate matter in ambient air in Beijing residents with and without pre-diabetes.

OBJECTIVE: Exposure to particulate matter (PM) is a risk factor to diabetes, but the underlying mechanism is unclear. Adipokines play important roles in glucose metabolism. This study examined the associations between short-term exposure to ambient PM and adipokine levels and evaluated whether metabolic disorders could enhance susceptibility to PM-induced health effects. RESEARCH DESIGN AND METHODS: In a panel study (SCOPE, Study Comparing the Cardiometabolic and Respiratory Effects of Air Pollution Exposure on Healthy and Pre-diabetic Individuals) in Beijing, China, 60 pre-diabetic individuals and 60 healthy controls completed two to seven clinical visits. The associations between serum adiponectin, leptin, and resistin levels and the moving average (MA) mass concentration of PM2.5 and number concentrations of ultrafine particles (UFP) and accumulation-mode particles (AMP) during the 1-14 days prior to clinical visits, and the effects of metabolic disorders on any such associations, were evaluated using a linear mixed-effects model. RESULTS: Short-term exposure to ambient UFP and AMP was inversely associated with adipokine levels at 1-14 days prior to clinical visits. For example, each IQR increment in 1 day MA UFP exposure (6.0×103/cm3) was associated with -14.0% (95% CI -20.9%, -6.4%), -6.6% (95% CI -12.4%, -0.4%), and -8.5% (95% CI -14.5%, -2.2%) changes in adiponectin, leptin, and resistin levels, respectively. There was no significant association between adipokine levels and PM2.5 exposure. UFP and AMP exposure was associated with a greater decrease in adiponectin level and a weaker change in leptin level among participants with high insulin resistance levels. Glucose status did not modify PM-induced changes in adipokine levels. CONCLUSION: High level of insulin resistance could aggravate the adverse metabolic impact of exposure to UFP and AMP.

A rapid and high-throughput approach to quantify non-esterified oxylipins for epidemiological studies using online SPE-LC-MS/MS.

Oxylipins are highly bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs) and have fundamental roles in a diverse set of homeostatic and inflammatory processes. Current targeted methods of analyzing oxylipins require long runtimes and laborious sample preparation, limiting their application to epidemiological studies. Here, we report the development of an online solid-phase extraction-liquid chromatography-triple quadrupole mass spectrometry (online SPE-LC-MS/MS) method to quantify 49 non-esterified oxylipins and PUFAs, including prostanoids, leukotrienes, lipoxins, resolvins, hydroxy PUFAs, epoxy PUFAs, and their PUFA precursors, in 50-µL samples of human serum. The new method was validated in terms of linearity, lower limits of quantification, recovery, precision, and matrix effects. The limits of quantification were in the range of 0.18 to 9 pg for oxylipins. A single 11.5-min analysis enabled the accurate (80-120% recovery), precise, and reproducible (RSD < 15%) quantification of 32 analytes at three spiked concentrations (0.1, 1, 5 ng/mL), demonstrating the suitability of this method for large-scale epidemiological studies. We successfully applied it to rapidly analyze a total of 565 serum samples from prediabetic and healthy individuals in a nested case-control panel study. Oxylipin concentrations were quantified within a range similar to those of previously published articles. Application of this approach to both healthy and prediabetic subjects found that several circulating hydroxy PUFAs, including LTB4, 12-HEPE, 15(S)-HETE, and 17-HDHA, were negatively associated with fasting glucose levels, indicating decreased anti-inflammatory activity and impaired glucose tolerance in diabetes progression. This new approach provides a means for high-throughput analyses of non-esterified oxylipins for epidemiological studies and will help unravel the intricate interactions of the oxylipin cascade and accelerate our understanding of the biological regulation of these important lipid mediators in human disease.

Respiratory Inflammation and Short-Term Ambient Air Pollution Exposures in Adult Beijing Residents with and without Prediabetes: A Panel Study.

BACKGROUND: Accumulating evidence suggests that individuals with glucose metabolism disorders are susceptible to mortality associated with fine particles. However, the mechanisms remain largely unknown. OBJECTIVES: We examined whether particle-associated respiratory inflammation differed between individuals with prediabetes and healthy control participants. METHODS: Based on a panel study [A prospective Study COmparing the cardiometabolic and respiratory effects of air Pollution Exposure on healthy and prediabetic individuals (SCOPE)] conducted in Beijing between August 2013 and February 2015, fractional exhaled nitric oxide (FeNO) was measured from 112 participants at two to seven visits to indicate respiratory inflammation. Particulate pollutants-including particulate matter with an aerodynamic diameter of ≤2.5µm (PM2.5), black carbon (BC), ultrafine particles (UFPs), and accumulated-mode particles-were monitored continuously at a single central monitoring site. Linear mixed-effects models were used to estimate associations between ln-FeNO with pollutant concentrations at individual 1-h lags (up to 24 h) and with average concentrations at 8 and 24 h before the clinical visit. We evaluated glucose metabolism disorders as a potential modifier by comparing associations between participants with high vs. low average fasting blood glucose (FBG) and homeostasis model assessment insulin resistance (HOMA-IR) levels. RESULTS: FeNO was positively associated with all pollutants, with the strongest associations for an interquartile range increase in 1-h lagged exposures (ranging from 21.3% for PM2.5 to 74.7% for BC). Associations differed significantly according to average HOMA-IR values when lagged 6-18 h for PM2.5, 15-19 h for BC, and 6-15 h for UFPs, with positive associations among those with HOMA-IR≥1.6 while associations were closer to the null or inverse among those with HOMA-IR<1.6. Associations between PM2.5 and FeNO were consistently higher among individuals with average FBG≥6.1 mmol/L vs. low FBG, with significant differences for multiple hourly lags. DISCUSSION: Glucose metabolism disorders may aggravate respiratory inflammation following exposure to ambient particulate matter. https://doi.org/10.1289/EHP4906.

Association of internal exposure to polycyclic aromatic hydrocarbons with inflammation and oxidative stress in prediabetic and healthy individuals.

Polycyclic aromatic hydrocarbons (PAHs) are key air pollutants that may contribute to the risk of numerous diseases by inducing inflammation and oxidative stress. Individuals with metabolic disorders may be more susceptible to PAH-induced inflammation and oxidative stress. To test this hypothesis, we designed a panel study involving 60 patients with pre-type 2 diabetes (pre-T2D) and 60 reference participants, and conducted up to seven repeated clinical examinations. Urinary metabolites of PAHs (i.e., OH-PAHs), measured as indicators of total PAH exposure, showed significant associations with markers of respiratory and systemic inflammation, including exhaled nitric oxide, interleukin (IL)-6 in exhaled breath condensate, and blood IL-2 and IL-8 levels and leucocyte count. The most significant effect was on urinary malondiadehyde (MDA), a marker of lipid peroxidation; a onefold increase of OH-PAHs was associated with 9.2-46.0% elevation in MDA in pre-T2D participants and 9.8-31.2% increase in healthy references. Pre-T2D participants showed greater increase in MDA, suggesting that metabolic disorder enhanced the oxidative damage induced by PAH exposure. This study revealed the association between PAH exposure and markers of inflammation and oxidative stress, and the enhanced responses of pre-T2D patients suggested that individuals with metabolic disorders were more susceptible to the adverse health effects of PAH exposure.

Susceptibility of prediabetes to the health effect of air pollution: a community-based panel study with a nested case-control design.

BACKGROUND: Recent studies suggest that people with diabetes or who are at risk of developing diabetes, i.e. prediabetic (preDM), are potentially susceptible to air pollution, but the underlying mechanisms remain unclear because the existing epidemiological studies did not include healthy control groups and only focused on limited health outcomes. We hypothesized that acute exposure to ambient fine particles (PM2.5) will lead to enhanced pulmonary and cardiometabolic changes in preDM than healthy individuals. METHODS: We recruited 60 preDM and 60 healthy individuals from a community of 22,343 adults in Beijing China, and arranged each subject to complete up to seven repeated clinical visits with measures of 6 cardiopulmonary biomarkers, 6 cytokines, 4 blood pressure and endothelial function outcomes and 4 glucose metabolism biomarkers.. Moving averaged daily ambient PM2.5 in preceding 1-14 days was matched to each subject and the PM2.5 associated effect on multiple biomarkers was estimated and compared between PreDM and healthy subjects based on linear mixed effect model. RESULTS: All the subjects exhibited significant acute elevation of exhaled nitric oxide, white blood cells, neutrophils, interleukin-1α, and glycated haemoglobin with increased exposure to PM2.5. PreDM subjects had significant stronger adverse changes compared to healthy subjects in 6 cardiometabolic biomarkers, namely, interleukin-2, interleukin-8, systolic and diastolic blood pressure, augmentation pressure, and glucose. The maximum elevation of these 6 biomarkers in PreDM subjects were 8.6% [CI: 4.1-13.3%], 10.0% [CI: 3.9-16.4%], 1.9% [CI: 0.2-3.6%], 1.2% [CI: - 0.1-2.4%], 5.7% [CI: - 0.1-11.8%], 2.4% [CI: 0.7-4.2%], respectively, per an interquartile increase of ambient PM2.5 (61.4 µg m- 3) throughout the exposure window of the preceding 1-14 days. No significant difference was observed for the changes in pulmonary biomarkers between the two groups. CONCLUSIONS: PreDM individuals are more susceptible to the acute cardiometabolic effect of air pollution than the healthy individuals. A considerable public health burden can be inferred, given the high prevalence of prediabetes and the ubiquity of air pollution in China and worldwide.