Desipramine ameliorates fine particulate matter-induced hepatic insulin resistance by modulating the ceramide metabolism in mice.

Recent research has highlighted a correlation between exposure to ambient fine particulate matter (PM2.5) and the development of systemic insulin resistance (IR) along with an elevated risk of diabetes. Ceramide has emerged as one of the pathogenic mechanisms contributing to IR. The inhibition of acid sphingomyelinase (ASMase) activity by desipramine (DES) has been shown to effectively reduce ceramide levels. In the present study, 24 female C57BL/6 N mice were randomized into one of the four groups: the filtered air exposure (FA) group, the concentrated PM2.5 exposure (PM) group, the concentrated PM2.5 treated with low-dose DES (DL) group, and the concentrated PM2.5 treated with high-dose DES (DH) group. The PM, DL and DH groups were exposed to PM2.5 for an 8-week period within a whole-body exposure system. The study encompassed extensive examinations of glucose homeostasis, liver lipid profile, ceramide pathway, and insulin signaling pathway. Our results demonstrated that PM2.5 exposure caused impaired glucose tolerance, elevated ceramide levels, increased phosphorylation PP2A, reduced Akt phosphorylation, and hindered GLUT2 expression. Remarkably, DES administration mitigated PM2.5-induced IR by effectively lowering ceramide levels. In conclusion, the reduction of ceramide levels by DES may be a promising therapeutic strategy for coping PM2.5-induced IR.

Ambient fine particulate matter and allergic symptoms in the middle-aged and elderly population: results from the PIFCOPD study.

BACKGROUND: The associations between short- and long-term exposure to ambient fine particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) and allergic symptoms in middle-aged and elderly populations remain unclear, particularly in China, where most cities have severe air pollution. METHODS: Participants (n = 10,142; age = 40-75 years) were recruited from ten regions in China from 2018 to 2021 for the Predictive Value of Inflammatory Biomarkers and Forced Expiratory Volume in 1 s (FEV1) for Chronic Obstructive Pulmonary Disease (PIFCOPD) study. Short-term (lag0 and lag0-7 day) and long-term (1-, 3- and 5-year) PM2.5 concentrations at residences were extracted from the air pollutant database known as Tracking Air Pollution (TAP) in China. Multivariate logistic regression models were used to estimate associations for short- and long-term PM2.5 exposure concentrations and long-term exposure models were additionally adjusted for short-term deviations. RESULTS: A 10 µg/m3 increase in PM2.5 on the day the allergic symptoms questionnaire was administered (lag0 day) was associated with higher odds of allergic nasal (1.09, 95% CI 1.05, 1.12) and eye symptoms (1.08, 95% CI 1.05, 1.11), worsening dyspnea caused by allergens (1.06, 95% CI 1.02, 1.10), and ≥ 2 allergic symptoms (1.07, 95% CI 1.03, 1.11), which was similar in the lag0-7 day concentrations. A 10 µg/m3 increase in the 1-year average PM2.5 concentration was associated with an increase of 23% for allergic nasal symptoms, 22% for eye symptoms, 20% for worsening dyspnea caused by allergens, and 21% for ≥ 2 allergic symptoms, similar to the 3- and 5-year average PM2.5 concentrations. These associations between long-term PM2.5 concentration and allergic symptoms were generally unchanged after adjustment for short-term deviations. CONCLUSIONS: Short- and long-term exposure to ambient PM2.5 was associated with an increased risk of allergic nasal and eye symptoms, worsening dyspnea caused by allergens, and ≥ 2 allergic symptoms. TRIAL REGISTRATION: Clinical trial ID: NCT03532893 (29 Mar 2018).

Long-term PM2.5 exposure disrupts corneal epithelial homeostasis by impairing limbal stem/progenitor cells in humans and rat models.

BACKGROUND: Limbal stem/progenitor cells (LSPCs) play a crucial role in maintaining corneal health by regulating epithelial homeostasis. Although PM2.5 is associated with the occurrence of several corneal diseases, its effects on LSPCs are not clearly understood. METHODS: In this study, we explored the correlation between PM2.5 exposure and human limbal epithelial thickness measured by Fourier-domain Optical Coherence Tomography in the ophthalmologic clinic. Long- and short-term PM2.5 exposed-rat models were established to investigate the changes in LSPCs and the associated mechanisms. RESULTS: We found that people living in regions with higher PM2.5 concentrations had thinner limbal epithelium, indicating the loss of LSPCs. In rat models, long-term PM2.5 exposure impairs LSPCs renewal and differentiation, manifesting as corneal epithelial defects and thinner epithelium in the cornea and limbus. However, LSPCs were activated in short-term PM2.5-exposed rat models. RNA sequencing implied that the circadian rhythm in LSPCs was perturbed during PM2.5 exposure. The mRNA level of circadian genes including Per1, Per2, Per3, and Rev-erbα was upregulated in both short- and long-term models, suggesting circadian rhythm was involved in the activation and dysregulation of LSPCs at different stages. PM2.5 also disturbed the limbal microenvironment as evidenced by changes in corneal subbasal nerve fiber density, vascular density and permeability, and immune cell infiltration, which further resulted in the circadian mismatches and dysfunction of LSPCs. CONCLUSION: This study systematically demonstrates that PM2.5 impairs LSPCs and their microenvironment. Moreover, we show that circadian misalignment of LSPCs may be a new mechanism by which PM2.5 induces corneal diseases. Therapeutic options that target circadian rhythm may be viable options for improving LSPC functions and alleviating various PM2.5-associated corneal diseases.

High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages.

BACKGROUND: Epidemiological studies have demonstrated that individuals with preexisting conditions, including diabetes mellitus (DM), are more susceptible to air pollution. However, the underlying mechanisms remain unclear. In this study, we proposed that a high glucose setting enhances ambient fine particulate matter (PM2.5)-induced macrophage activation and secretion of the proinflammatory cytokine, IL-1ß, through activation of the NLRP3 inflammasome, altering the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). RESULTS: Exposure of mouse alveolar macrophages to non-cytotoxic doses of PM2.5 led to upregulation of IL-1ß, activation of the NLRP3 inflammasome, increased nuclear translocation of the transcription factor NF-κB, increased generation of reactive oxygen species (ROS), and increased expression and enzymatic activity of MMP-9; these effects were enhanced when cells were pretreated with high glucose. However, pretreatment in a high glucose setting alone did not induce significant changes. ROS generation following PM2.5 exposure was abolished when cells were pretreated with ROS scavengers such as Trolox and superoxide dismutase (SOD), or with an NADPH oxidase inhibitor, DPI. Pretreatment of cells with DPI attenuated the effects of a high glucose setting on PM2.5-induced upregulation of IL-1ß, activation of the NLRP3 inflammasome, and nuclear translocation of NF-κB. In addition, enhancement of PM2.5-induced expression and enzymatic activity of MMP-9 following high glucose pretreatment was not observed in primary alveolar macrophages obtained from NLRP3 or IL-1R1 knockout (KO) mice, where pro-IL-1ß cannot be cleaved to IL-1ß or cells are insensitive to IL-1ß, respectively. CONCLUSIONS: This study demonstrated that exposure of mouse alveolar macrophages to PM2.5 in a high glucose setting enhanced PM2.5-induced production of IL-1ß through activation of the NLRP3 inflammasome and nuclear translocation of NF-κB due to PM2.5-induced oxidative stress, leading to MMP-9 upregulation. The key role of NADPH oxidase in PM2.5-induced ROS generation and activation of the IL-1ß secretion pathway and the importance of IL-1ß secretion and signaling in PM2.5-induced increases in MMP-9 enzymatic activity were also demonstrated. This study provides a further understanding of the potential mechanisms underlying the susceptibility of individuals with DM to air pollution and suggests potential therapeutic targets.

PM2.5 exposure triggers cell death through lysosomal membrane permeabilization and leads to ferroptosis insensitivity via the autophagy dysfunction/p62-KEAP1-NRF2 activation in neuronal cells.

PM2.5 exposure can be associated with the onset of neurodegenerative diseases, with oxidative stress-induced cellular homeostasis disruption and cell death as one of the main mechanisms. However, the exact cellular and molecular processes are still rarely investigated. Autophagy and KEAP1-NRF2 (Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2 related factor 2) signaling pathway are two main cellular defense systems for maintaining cellular homeostasis and resisting oxidative stress. In this study, we primarily investigated the role of autophagy and KEAP1-NRF2 in regulating cell death resulting from PM2.5 exposure in mouse neuroblastoma N2a cells. Our results showed that PM2.5 exposure disrupted autophagic flux by impairing lysosomal function, including lysosomal alkalinization, increased lysosome membrane permeabilization (LMP), and Cathepsin B release. Furthermore, dysregulated autophagy enhances NRF2 activity in a p62-dependent manner, which then initiates the expression of a series of antioxidant genes and increases cellular insensitivity to ferroptosis. Meanwhile, autophagy dysfunction impairs the intracellular degradation of ferroptosis related proteins such as GPX4 and ferritin. As these proteins accumulate, cells also become less sensitive to ferroptosis. LMP-associated cell death may be the main mechanism of PM2.5-induced N2a cytotoxicity. Our results may provide insights into the mechanisms of PM2.5-induced neurotoxicity and predict effective prevention and treatment strategies.

Role of PM2.5 in the development and progression of COPD and its mechanisms.

BACKGROUND: A multitude of epidemiological studies have shown that ambient fine particulate matter 2.5 (diameter < 2.5um; PM2.5) was associated with increased morbidity and mortality of chronic obstructive pulmonary disease (COPD). However, the underlying associated mechanisms have not yet been elucidated. We conducted this study to investigate the role of PM2.5 in the development of COPD and associated mechanisms. METHODS: We firstly conducted a cross-sectional study in Chinese han population to observe PM2.5 effects on COPD morbidity. Then, in vitro, we incubated human bronchial epithelial cells to different concentrations of PM2.5 for 24 h. The expression levels of IL-6 and IL-8 were detected by ELISA and the levels of MMPs, TGF-ß1, fibronectin and collagen was determined by immunoblotting. In vivo, we subjected C57BL/6 mice to chronic prolonged exposure to PM2.5 for 48 weeks to study the influence of PM2.5 exposure on lung function, pulmonary structure and inflammation. RESULTS: We found that the effect of PM2.5 on COPD morbidity was associated with its levels and that PM2.5 and cigarette smoke could have a synergistic impact on COPD development and progression. Both vitro and vivo studies demonstrated that PM2.5 exposure could induce pulmonary inflammation, decrease lung function, and cause emphysematous changes. Furthermore, PM2.5 could markedly aggravated cigarette smoke-induced changes. CONCLUSIONS: In short, we found that prolonged chronic exposure to PM2.5 resulted in decreased lung function, emphysematous lesions and airway inflammation. Most importantly, long-term PM2.5 exposure exacerbateed cigarette smoke-induced changes in COPD.

Ambient PM2.5 causes lung injuries and coupled energy metabolic disorder.

Ambient fine particulate matter (PM2.5) is a challenge to public health worldwide. Although increasing numbers of recent epidemiological studies have emphasized the critical role of PM2.5 in promoting respiratory diseases, the precise mechanism behind PM2.5-mediated lung obstruction remains obscure. In the present study, we analyzed lung structure and function and further investigated mitochondrial morphology and transcription-modulated energy metabolism in mice following PM2.5 aspiration. The results showed that PM2.5 exposure reduced pulmonary function and induced severe pathological alterations, including alveolar endothelial disruption and airway obstruction. Based on ultrastructural observations, we also found mitochondrial vacuolation and mitochondrial membrane rupture in alveolar type II epithelial cells. Importantly, the abnormality of mitochondrial structure was coupled with energy metabolism disorders, as evidenced by the decrease in ATP levels, the accumulation of pyruvate and lactate content, and the altered transcription of related genes. Moreover, the reduction in mitochondrial markers, including PGC-1α, NRF-1, and TFAM, were involved in mitochondrial dysfunction. These findings suggest that energy metabolic disorders and mitochondrial dysfunction may be the important contributors to pulmonary injuries in response to PM2.5 exposure, indicating possible targets for protection and therapy in polluted areas.

Ambient fine particulate matters induce cell death and inflammatory response by influencing mitochondria function in human corneal epithelial cells.

Ambient fine particulate matter (AFP) is a main risk factor for the cornea as ultraviolet light. However, the mechanism of corneal damage following exposure to AFP has been poorly understood. In this study, we first confirmed that AFP can penetrate the cornea of mice, considering that two-dimensional cell culture systems are limited in reflecting the situation in vivo. Then, we investigated the toxic mechanism using human corneal epithelial (HCET) cells. At 24h after exposure, AFP located within the autophagosome-like vacuoles, and cell proliferation was clearly inhibited in all the tested concentration. Production of ROS and NO and secretion of pro-inflammatory cytokines were elevated in a dose-dependent manner. Additionally, conversion of LC3B from I-type to II-type and activation of caspase cascade which show autophagic- and apoptotic cell death, respectively, were observed in cells exposed to AFP. Furthermore, AFP decreased mitochondrial volume, inhibited ATP production, and altered the expression of metabolism-related genes. Taken together, we suggest that AFP induces cell death and inflammatory response by influencing mitochondrial function in HCET cells. In addition, we recommend that stringent air quality regulations are needed for eye health.

Burden of disease attributable to ambient fine particulate matter exposure in Taiwan.

BACKGROUND/PURPOSE: There is compelling epidemiological evidence that links air pollution to increased risk of mortality from cardiopulmonary disease and lung cancer. We quantified the burden of mortality attributable to ambient fine particulate matter (PM2.5) among the Taiwanese population in 2014 at the national and subnational levels. METHODS: Subnational PM2.5 exposure levels were obtained from Taiwan Air Quality Monitoring Network. Relative risks were derived from a previously developed exposure-response model. Population attributable fraction for cause-specific mortality was estimated at the county level using the estimated ambient PM2.5 concentrations and the relative risk functions. RESULTS: In 2014, PM2.5 accounted for 6282 deaths [95% confidence interval (CI), 5716-6847], from ischemic heart disease (2244 deaths; 95% CI, 2015-2473), stroke (2140 deaths; 95% CI, 1760-2520), lung cancer (1252 deaths; 95% CI, 995-1509), and chronic obstructive pulmonary disease (645 deaths; 95% CI, 418-872). Nationally, the population attributable mortality fraction of PM2.5 for the four disease causes was 18.6% (95% CI, 16.9-20.3%). Substantial geographic variation in PM2.5 attributable mortality fraction was found; the percentage of deaths attributable to PM2.5 ranged from 8.7% in Hualian County to 21.8% in Yunlin County. In terms of absolute number of deaths, New Taipei and Kaohsiung cities had the largest number of deaths associated with PM2.5 (874 and 829 deaths, respectively) among all cities and counties. CONCLUSION: Ambient PM2.5 pollution is a major mortality risk factor in Taiwan. Aggressive and multisectorial intervention strategies are urgently needed to bring down the impact of air pollution on environment and health.

Changes on Stroke Burden Attributable to Ambient Fine Particulate Matter in China.

Objective: In recent decades, China has implemented a series of policies to address air pollution. We aimed to assess the health effects of these policies on stroke burden attributable to ambient fine particulate matter (PM 2.5). Methods: Joinpoint regression was applied to explore the temporal tendency of stroke burden based on data from the Global Burden of Disease 2019 study. Results: The age-standardized rates of disability-adjusted life year (DALY) for stroke attributable to ambient PM 2.5 in China, increased dramatically during 1990-2012, subsequently decreased at an annual percentage change (APC) of -1.98 [95% confidence interval ( CI): -2.26, -1.71] during 2012-2019. For ischemic stroke (IS), the age-standardized DALY rates doubled from 1990 to 2014, and decreased at an APC of -0.83 (95% CI: -1.33, -0.33) during 2014-2019. Intracerebral hemorrhage (ICH) showed a substantial increase in age-standardized DALY rates from 1990 to 2003, followed by declining trends, with APCs of -1.46 (95% CI: -2.74, -0.16) during 2003-2007 and -3.33 (95% CI: -3.61, -3.06) during 2011-2019, respectively. Conversely, the age-standardized DALY rates for subarachnoid hemorrhage (SAH) generally declined during 1990-2019. Conclusion: Our results clarified the dynamic changes of the ambient PM 2.5-attributable stroke burden in China during 1990-2019, highlighting the health effects of air quality improvement policies.

Long-term exposure to ambient PM2.5 and its constituents is associated with MAFLD.

Background & Aims: Existing evidence suggests that long-term exposure to ambient fine particulate pollution (PM2.5) may increase metabolic dysfunction-associated fatty liver disease (MAFLD) risk. However, there is still limited evidence on the association of PM2.5 constituents with MAFLD. Therefore, this study explores the associations between the five main chemical constituents of PM2.5 and MAFLD to provide more explicit information on the liver exposome. Methods: A total of 76,727 participants derived from the China Multi-Ethnic Cohort, a large-scale epidemic survey in southwest China, were included in this study. Multiple linear regression models were used to estimate the pollutant-specific association with MAFLD. Weighted quantile sum regression was used to evaluate the joint effect of the pollutant-mixture on MAFLD and identify which constituents contribute most to it. Results: Three-year exposure to PM2.5 constituents was associated with a higher MAFLD risk and more severe liver fibrosis. Odds ratios for MAFLD were 1.480, 1.426, 1.294, 1.561, 1.618, and 1.368 per standard deviation increase in PM2.5, black carbon, organic matter, ammonium, sulfate, and nitrate, respectively. Joint exposure to the five major chemical constituents was also positively associated with MAFLD (odds ratio 1.490, 95% CI 1.360-1.632). Nitrate contributed most to the joint effect of the pollutant-mixture. Further stratified analyses indicate that males, current smokers, and individuals with a high-fat diet might be more susceptible to ambient PM2.5 exposure than others. Conclusions: Long-term exposure to PM2.5 and its five major chemical constituents may increase the risk of MAFLD. Nitrate might contribute most to MAFLD, which may provide new clues for liver health. Males, current smokers, and participants with high-fat diets were more susceptible to these associations. Impact and implications: This large-scale epidemiologic study explored the associations between constituents of fine particulate pollution (PM2.5) and metabolic dysfunction-associated fatty liver disease (MAFLD), and further revealed which constituents play a more important role in increasing the risk of MAFLD. In contrast to previous studies that examined the effects of PM2.5 as a whole substance, this study carefully explored the health effects of the individual constituents of PM2.5. These findings could (1) help researchers to identify the specific particles responsible for hepatotoxicity, and (2) indicate possible directions for policymakers to efficiently control ambient air pollution, such as targeting the sources of nitrate pollution.

Distinct brain lipid signatures in response to low-level PM2.5 exposure in a 3xTg-Alzheimer's disease mouse inhalation model.

Fine particulate matter (PM2.5) poses a significant risk to human health. The molecular mechanisms underlying low-level PM2.5-induced neurotoxicity in the central nervous system remain unclear. In addition, changes in lipids in response to PM2.5 exposure have not yet been fully elucidated. In this study, 3xTg-Alzheimer's disease (AD) mice experienced continuous whole-body exposure to non-concentrated PM2.5 for three consecutive months, while control mice inhaled particulate matter-filtered air over the same time span. A liquid chromatography-mass spectrometry-based lipidomic platform was used to determine the distinct lipid profiles of various brain regions. The average PM2.5 concentration during the exposure was 11.38 µg/m3, which was close to the regulation limits of USA and Taiwan. The partial least squares discriminant analysis model showed distinct lipid profiles in the cortex, hippocampus, and olfactory bulb, but not the cerebellum, of mice in the exposure group. Increased levels of fatty acyls, glycerolipids, and sterol lipids, as well as the decreased levels of glycerophospholipids and sphingolipids in PM2.5-exposed mouse brains may be responsible for the increased energy demand, membrane conformation, neuronal loss, antioxidation, myelin function, and cellular signaling pathways associated with AD development. Our research suggests that subchronic exposure to low levels of PM2.5 may cause neurotoxicity by changing the lipid profiles in a susceptible model. Lipidomics is a powerful tool to study the early effects of PM2.5-induced AD toxicity.

The short-term association of ambient fine particulate air pollution with hypertension clinic visits: A multi-community study in Guangzhou, China.

BACKGROUND: The association of ambient fine particulate pollution with daily outpatient clinic visits (OCV) for hypertension in China remains to be investigated. OBJECTIVES: This study aimed to examine short-term impacts of exposure to fine particulate matter of aerodynamic diameter < 2.5µm (PM2.5) on daily OCV for hypertension, using a large-scale multi-center community database in Guangzhou, one of the most densely-populated cities in Southern China. METHODS: We collected a total of 28,548 individual records of OCV from 22 community healthcare facilities in Guangzhou from January 1st to May 7th 2020. Hourly data on air pollutants and daily information on meteorological factors were obtained. According to the World Health Organization air-quality guidelines, daily excessive concentration hours (DECH) was calculated. PM2.5 daily mean, hourly-peak concentration and DECH were used as the exposure variables. Based on a case-time-control design, the Cox regression model was applied to evaluate the short-term relative risks (RR) of daily OCV for hypertension. Sensitivity analyses were conducted, with nitrogen dioxide, sulfur dioxide, carbon monoxide, and ozone being adjusted. RESULTS: Daily mean and hourly-peak of PM2.5 were significantly associated with daily OCV for hypertension, while weaker associations were observed for DECH. The estimated RRs at lag day 0 were 1.039 (95% confidence interval [CI]: 1.037, 1.040), 1.851 (95%CI: 1.814, 1.888), and 1.287 (95%CI: 1.276, 1.298), respectively, in association with a 1-unit increase in DECH, daily mean, and hourly-peak concentration of PM2.5. For the lagged effect, lag4 models estimated the greatest RRs for PM2.5 DECH and hourly-peak, whereas a lag2 model produced the highest for PM2.5 daily mean. DISCUSSION: This study consolidates the evidence for a positive correlation between ambient PM2.5 exposure and risks of hypertensive OCV. It also provides profound insight regarding planning for health services needs and establishing early environmental responses to the worsening air pollution in the communities.

Ambient fine particulate matter air pollution and the risk of hospitalization among COVID-19 positive individuals: Cohort study.

BACKGROUND: Ecologic analyses suggest that living in areas with higher levels of ambient fine particulate matter air pollution (PM2.5) is associated with higher risk of adverse COVID-19 outcomes. Studies accounting for individual-level health characteristics are lacking. METHODS: We leveraged the breadth and depth of the US Department of Veterans Affairs national healthcare databases and built a national cohort of 169,102 COVID-19 positive United States Veterans, enrolled between March 2, 2020 and January 31, 2021, and followed them through February 15, 2021. Annual average 2018 PM2.5 exposure, at an approximately 1 km2 resolution, was linked with residential street address at the year prior to COVID-19 positive test. COVID-19 hospitalization was defined as first hospital admission between 7 days prior to, and 15 days after, the first COVID-19 positive date. Adjusted Poisson regression assessed the association of PM2.5 with risk of hospitalization. RESULTS: There were 25,422 (15.0%) hospitalizations; 5,448 (11.9%), 5,056 (13.0%), 7,159 (16.1%), and 7,759 (19.4%) were in the lowest to highest PM2.5 quartile, respectively. In models adjusted for State, demographic and behavioral factors, contextual characteristics, and characteristics of the pandemic a one interquartile range increase in PM2.5 (1.9 µg/m3) was associated with a 10% (95% CI: 8%-12%) increase in risk of hospitalization. The association of PM2.5 and risk of hospitalization among COVID-19 individuals was present in each wave of the pandemic. Models of non-linear exposure-response suggested increased risk at PM2.5 concentrations below the national standard 12 µg/m3. Formal effect modification analyses suggested higher risk of hospitalization associated with PM2.5 in Black people compared to White people (p = 0.045), and in those living in socioeconomically disadvantaged neighborhoods (p < 0.001). CONCLUSIONS: Exposure to higher levels of PM2.5 was associated with increased risk of hospitalization among COVID-19 infected individuals. The risk was evident at PM2.5 levels below the regulatory standards. The analysis identified those of Black race and those living in disadvantaged neighborhoods as population groups that may be more susceptible to the untoward effect of PM2.5 on risk of hospitalization in the setting of COVID-19.

Ambient fine particulate matter disrupts hepatic circadian oscillation and lipid metabolism in a mouse model.

Emerging evidence has shown that exposure to ambient fine particulate matter (PM2.5) is associated with hepatic lipid accumulation. However, the underlying mechanism is not fully characterized yet. Autonomous circadian clock in the liver plays a fundamental role in maintaining lipid metabolism homeostasis. In this study, we evaluated the effects of ambient PM2.5 exposure on the expression of hepatic circadian clock genes and expression rhythm of genes associated with lipid metabolism in mice liver. Male C57BL/6 mice were randomly assigned to ambient PM2.5 or filtered air for 10 weeks via a whole body exposure system. We found that the liver mass was reduced significantly at zeitgeber time (ZT) 8 in mice exposed to PM2.5 but not levels or circadian rhythm of hepatic triglycerides or free fatty acid (FFA). In addition, exposure to PM2.5 led to enhanced expression of bmal1 at ZT0/24, cry1 at ZT16 and rev-erbα at ZT4 and ZT8. Furthermore, the expression of pparα was enhanced in mice liver at ZT4 and ZT8 after PM2.5 exposure, with upregulation of pparα-mediated genes responsible for fatty acid transport and oxidation. Finally, the expression of rate-limiting enzymes for lipid synthesis was all significantly increased in the liver of PM2.5 exposed mice at ZT12. Therefore, the present study provides new perspectives for revealing the etiology of hepatic lipid metabolism abnormality from PM2.5-induced circadian rhythm disorder.

Brain lipid profiles in the spontaneously hypertensive rat after subchronic real-world exposure to ambient fine particulate matter.

Recent studies have illustrated an association between ambient fine particulate matter (PM2.5) exposure and neuronal toxicity in epidemiological studies and animal models. However, the possible molecular effects on brains under real-world exposure to PM2.5 remain unclear. In this pilot study, male spontaneously hypertensive rats were whole-bodily exposed to ambient air from the outdoor environment of Taipei City for 3 months, while the control rats inhaled HEPA-filtered air. The PM2.5-induced phosphatidylcholine and sphingomyelin profiles in the hippocampus, cortex, medulla, cerebellum, and olfactory bulb were assessed by mass spectrometry (MS)-based lipidomics. Partial least squares discriminant analysis (PLS-DA) and the Wilcoxon rank sum test were used to examine the lipid changes between the exposed and control groups. The PLS-DA models showed that phosphatidylcholine and sphingomyelin profiles of the PM2.5 exposure group were different from those of the control group in each brain region except the cortex. More lipid changes were found in the hippocampus, while fewer lipid changes were observed in the olfactory bulb. The lipid alteration in the hippocampus may strengthen membrane integrity, modulate signaling pathways, and avoid accumulation of lipofuscin to counter the PM2.5-induced stress. The lipid changes in the cortex and medulla may respond to PM2.5-induced injury and inflammation; while the lipid changes in the cerebellum were associated with neuron protection. This study suggests that the MS-based lipidomics is a powerful approach to discriminate the brain lipid profiles even at the environmental level of ambient PM2.5 and has the potential to suggest possible adverse health effects in long-term PM2.5 exposure studies.