Mianhua Zhong

Effect of Early Particulate Air Pollution Exposure on Obesity in Mice. Role of p47phox

Objective—To evaluate the role of early-life exposure to airborne fine particulate matter (diameter, <2.5 &mgr;m [PM2.5]) pollution on metabolic parameters, inflammation, and adiposity; and to investigate the involvement of oxidative stress pathways in the development of metabolic abnormalities. Methods and Results—PM2.5 inhalation exposure (6 h/d, 5 d/wk) was performed in C57BL/6 mice (wild type) and mice deficient in the cytosolic subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47phox (p47phox−/−) beginning at the age of 3 weeks for a duration of 10 weeks. Both groups were simultaneously fed a normal diet or a high-fat diet for 10 weeks. PM2.5-exposed C57BL/6 mice fed a normal diet exhibited metabolic abnormalities after exposure to PM2.5 or FA for 10 weeks. Consistent with insulin resistance, these abnormalities included enlarged subcutaneous and visceral fat contents, increased macrophage infiltration in visceral adipose tissue, and vascular dysfunction. Ex vivo-labeled and infused monocytes demonstrated increased adherence in the microcirculation of normal diet- or high-fat diet-fed PM2.5-exposed mice. p47phox−/− mice exhibited an improvement in parameters of insulin resistance, vascular function, and visceral inflammation in response to PM2.5. Conclusion—Early-life exposure to high levels of PM2.5 is a risk factor for subsequent development of insulin resistance, adiposity, and inflammation. Reactive oxygen species generation by NADPH oxidase appears to mediate this risk.

Long-term Exposure to Ambient Fine Particulate Pollution Induces Insulin Resistance and Mitochondrial Alteration in Adipose Tissue

We have previously shown that chronic exposure to ambient fine particulate matter (less than 2.5 μm in aerodynamic diameter, PM₂.₅) pollution in conjunction with high-fat diet induces insulin resistance through alterations in inflammatory pathways. In this study, we evaluated the effects of PM₂.₅ exposure over a substantive duration of a rodents lifespan and focused on the impact of long-term exposure on adipose structure and function. C57BL/6 mice were exposed to PM₂.₅ or filtered air (FA) (6 h/day, 5 days/week) for duration of 10 months in Columbus, OH. At the end of the exposure, PM₂.₅-exposed mice demonstrated insulin resistance (IR) and a decrease in glucose tolerance compared with the FA-exposed group. Although there were no significant differences in circulating cytokines between PM₂.₅- and FA-exposed groups, circulating adiponectin and leptin were significantly decreased in PM₂.₅-exposed group. PM₂.₅ exposure also led to inflammatory response and oxidative stress as evidenced by increase of Nrf2-regulated antioxidant genes. Additionally, PM₂.₅ exposure decreased mitochondrial count in visceral adipose and mitochondrial size in interscapular adipose depots, which were associated with reduction of uncoupling protein 1 (UCP1) expression and downregulation of brown adipocyte-specific gene profiles. These findings suggest that long-term ambient PM₂.₅ exposure induces impaired glucose tolerance, IR, inflammation, and mitochondrial alteration, and thus, it is a risk factor for the development of type 2 diabetes.

Air pollution and cardiac remodeling: a role for RhoA/Rho-kinase

Exposure to ambient air pollution has been associated with increases in blood pressure. We have previously demonstrated activation of the Rho/Rho kinase pathway in experimental hypertension in rats. In this investigation, we evaluated the effects of particulate matter of < 2.5 microm (PM(2.5)) exposure on cardiovascular responses and remodeling and tested the effect of Rho kinase inhibition on these effects. C57BL/6 mice were exposed to concentrated ambient PM(2.5) or filtered air for 12 wk followed by a 14-day ANG II infusion in conjunction with fasudil, a Rho kinase antagonist, or placebo treatment. Blood pressure was monitored, followed by analysis of vascular function and ventricular remodeling indexes. PM(2.5) exposure potentiated ANG II-induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM(2.5) exposure along with increased expression of the guanine exchange factors (GEFs) PDZ-RhoGEF and p115 RhoGEF in PM(2.5)-exposed mice. Parallel with increased RhoA activation, PM(2.5) exposure increased ANG II-induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. In conclusion, PM(2.5) potentiates cardiac remodeling in response to ANG II through RhoA/Rho kinase-dependent mechanisms. These findings have implications for the chronic cardiovascular health effects of air pollution.

Source apportionment and elemental composition of PM2.5 and PM10 in Jeddah City, Saudi Arabia

This paper presents the first comprehensive investigation of PM2.5 and PM10 composition and sources in Saudi Arabia. We conducted a multi-week multiple sites sampling campaign in Jeddah between June and September, 2011, and analyzed samples by XRF. The overall mean mass concentration was 28.4 ± 25.4 μg/m3 for PM2.5 and 87.3 ± 47.3 μg/m3 for PM10, with significant temporal and spatial variability. The average ratio of PM2.5/PM10 was 0.33. Chemical composition data were modeled using factor analysis with varimax orthogonal rotation to determine five and four particle source categories contributing significant amount of for PM2.5 and PM10 mass, respectively. In both PM2.5 and PM10 sources were (1) heavy oil combustion characterized by high Ni and V; (2) resuspended soil characterized by high concentrations of Ca, Fe, Al, and Si; and (3) marine aerosol. The two other sources in PM2.5 were (4) Cu/Zn source; (5) traffic source identified by presence of Pb, Br, and Se; while in PM10 it was a mixed industrial source. To estimate the mass contributions of each individual source category, the CAPs mass concentration was regressed against the factor scores. Cumulatively, resuspended soil and oil combustion contributed 77 and 82% mass of PM2.5 and PM10, respectively.

Effects of Subchronic Exposures to Concentrated Ambient Particles (CAPs) in Mice: II. The Design of a CAPs Exposure System for Biometric Telemetry Monitoring

Abstract We modified, assembled, tested, and validated the versatile aerosol concentration enrichment system (VACES) developed by for use in a subchronic experiment that involved exposures of mice in vivo and of respiratory epithelial cells in vitro to concentrated ambient particles (CAPs). Since the labor-intensive nose-only exposure regimen is not an option in a long-term experiment, a whole-body exposure mouse chamber was designed specifically for use with the VACES. The exposure system consists of a stainless-steel (SS) tub with 32 cubicles (1 mouse per cubicle) separated by perforated SS sheets. The tops of these cubicles are covered with perforated plastic sheets to allow telemetry monitoring during the exposure. In each exposure chamber, perforated aluminum tubes are used to distribute CAPs evenly (within 2% difference) throughout the exposure chamber. The exhaust consists of perforated aluminum tubes covered with a urine shield. The modification to the original design of the VACES facilitated the operation of the system in a subchronic study. Mass flow controllers maintain a constant flow rate into the exposure chambers. For a sham control exposure, the identical system is used, except that a HEPA filter at the inlet to the VACES removes 98% of ambient particles. The entire system allows for simultaneous exposure of 64 mice to CAPs, with an equal number of sham-exposed mice as controls. Telemetry receivers have been modified so that 16 mice per group with electrocardiograph (EKG) transmitters can be monitored during exposure. Furthermore, a BioSampler is used to collect CAPs (one sample per day) for the in vitro exposures. In this article, the assessments of flow and particle distribution of the exposure chamber as well as the performance of the system during the subchronic exposure experiment are described.

Atherosclerosis lesion progression during inhalation exposure to environmental tobacco smoke: A comparison to concentrated ambient air fine particles exposure

Environmental tobacco smoke (ETS) and ambient air fine particulate matter (PM2.5) are both complex mixtures that have important adverse effects on the cardiovascular system. Although exposures to these complex mixtures have been studied individually, direct comparisons between the two has not been performed. In this study, the authors employed a novel, noninvasive ultrasound biomicroscopy method (UBM) to assess the effects of long-term, low-concentration inhalations of side-stream smoke (SS) and concentrated ambient PM2.5 (CAPs) on plaque progression. ApoE−/− mice (n = 8/group) on high-fat chow (HFC), or normal chow (NC), were exposed to SS (PM = 450 µg/m3) or filtered air (FA) for 6 h/day, 5 days/week, for 6 months; CAPs exposure was at 134 µg/m3 (NC only). Mortality during the SS exposure was greater in the HFC than in the NC, and SS significantly enhanced the effects of diet. No mortality was observed in CAPs-exposed mice. At 4 and 6 months, SS produced the greatest change in plaque area in the left common carotid artery (CCA) in HFC as compared to FA or NC, but not in the brachiocephalic artery. In contrast, CAPs exposure significantly enhanced plaque areas in brachiocephalic and left CCA at 3 and 6 months of exposure. The effect of SS was comparable in magnitude to that produced by CAPs at an average PM2.5 mass concentration that was only 30% as high. In light of the employment of the same animal model, uniform inhalation exposure protocols, time schedules, a noninvasive monitoring protocol, and a parallel study design, these findings have broad applicability.

The Role of Metal Components in the Cardiovascular Effects of PM2.5

Exposure to ambient fine particulate matter (PM2.5) increases risks for cardiovascular disorders (CVD). However, the mechanisms and components responsible for the effects are poorly understood. Based on our previous murine exposure studies, a translational pilot study was conducted in female residents of Jinchang and Zhangye, China, to test the hypothesis that specific chemical component of PM2.5 is responsible for PM2.5 associated CVD. Daily ambient and personal exposures to PM2.5 and 35 elements were measured in the two cities. A total of 60 healthy nonsmoking adult women residents were recruited for measurements of inflammation biomarkers. In addition, circulating endothelial progenitor cells (CEPCs) were also measured in 20 subjects. The ambient levels of PM2.5 were comparable between Jinchang and Zhangye (47.4 and 54.5µg/m3, respectively). However, the levels of nickel, copper, arsenic, and selenium in Jinchang were 82, 26, 12, and 6 fold higher than Zhangye, respectively. The levels of C-reactive protein (3.44±3.46 vs. 1.55±1.13), interleukin-6 (1.65±1.17 vs. 1.09±0.60), and vascular endothelial growth factor (117.6±217.0 vs. 22.7±21.3) were significantly higher in Jinchang. Furthermore, all phenotypes of CEPCs were significantly lower in subjects recruited from Jinchang than those from Zhangye. These results suggest that specific metals may be important components responsible for PM2.5-induced cardiovascular effects and that the reduced capacity of endothelial repair may play a critical role.

Gene expression profiling and pathway analysis of human bronchial epithelial cells exposed to airborne particulate matter collected from Saudi Arabia

Epidemiological studies have established a positive correlation between human mortality and increased concentration of airborne particulate matters (PM). However, the mechanisms underlying PM related human diseases, as well as the molecules and pathways mediating the cellular response to PM, are not fully understood. This study aims to investigate the global gene expression changes in human cells exposed to PM(10) and to identify genes and pathways that may contribute to PM related adverse health effects. Human bronchial epithelial cells were exposed to PM(10) collected from Saudi Arabia for 1 or 4 days, and whole transcript expression was profiled using the GeneChip human gene 1.0 ST array. A total of 140 and 230 genes were identified that significantly changed more than 1.5 fold after PM(10) exposure for 1 or 4 days, respectively. Ingenuity Pathway Analysis revealed that different exposure durations triggered distinct pathways. Genes involved in NRF2-mediated response to oxidative stress were up-regulated after 1 day exposure. In contrast, cells exposed for 4 days exhibited significant changes in genes related to cholesterol and lipid synthesis pathways. These observed changes in cellular oxidative stress and lipid synthesis might contribute to PM related respiratory and cardiovascular disease.

Effect of co-exposure to nickel and particulate matter on insulin resistance and mitochondrial dysfunction in a mouse model

BackgroundIt has been well recognized that toxicity of fine ambient air particulate matter (PM2.5) may depend on its chemical constituents, including components such as soluble metals that may theoretically exert distinctive effects. We have recently demonstrated an important effect of PM2.5 on metabolic function. Since transition metals, such as nickel (Ni), represent an important component of exposure in certain environments, and may significantly influence the toxicity of inhalational exposure, we investigated the effects of Ni as a variable component of ambient PM2.5 exposure.MethodsMale ApoE knockout mice were exposed to filtered air (FA), fine-sized nickel sulfate particles alone (Ni) at 0.44 μ g/m3, concentrated ambient air PM2.5 (CAPs) at a mean of 70 μ g/m3, or CAPs+Ni in Tuxedo, NY, 6 hours/day, 5 days/week, for 3 months.ResultsExposure to Ni, irrespective of co-exposure to CAPs, resulted in body weight gain, while exposure to CAPs+Ni significantly enhanced fasting glucose and worsened insulin resistance measures (HOMA-IR), when compared with exposure to CAPs alone. CAPs+Ni exposure induced a significant decrease in phosphorylation of AMP-activated protein kinase (AMPK) α. Exposure to Ni or CAPs+Ni significantly induced microcirculatory dysfunction and increased monocytic cell infiltration into lung and adipose, and decreased uncoupling protein 1 expression at gene and protein levels and several brown adipocyte-specific genes in adipose tissue.ConclusionsNi exposure has effects on metabolic and inflammatory parameters that are comparable to that of CAPs. Additionally, Ni synergistically exacerbates CAPs-induced adverse effects on some of, but not all of, these parameters, that may be mediated via the AMPK signaling pathway. These findings have important implications for inhaled transition metal toxicity that may exert synergistic effects with other PM2.5 components.

Association of Systemic Inflammation with Marked Changes in Particulate Air Pollution in Beijing in 2008

Many studies have linked ambient fine particulate matter (aerodynamic diameters less than 2.5 μm, PM₂.₅) air pollution to increased morbidity and mortality of cardiovascular diseases in the general population, but the biologic mechanisms of these associations are yet to be elucidated. In this study, we aimed to evaluate the relationship between daily variations in exposure to PM₂.₅ and inflammatory responses in mice during and for 2 months after the Beijing Olympic Games. Male C57BL/6 mice were exposed to Beijing PM₂.₅ or filtered air (FA) in 2008 during the 2 months of Beijing Olympic and Paralympic Games, and for 2 months after the end of the Games. During the Games, circulating monocyte chemoattractant protein 1 and interleukin 6 were increased significantly in the PM₂.₅ exposure group, when compared with the FA control group, although there were no significant inter-group differences in tumor necrosis factor-α or interferon-γ, or in macrophages, neutrophils or lymphocytes in the spleen or thymus between these 2 groups. However, macrophages were significantly increased in the lung and visceral fat with increasing PM₂.₅. After the Olympic Games, there were no significant PM₂.₅-associated differences for macrophages, neutrophils or lymphocytes in the thymus, but macrophages were significantly elevated in the lung, spleen, subcutaneous and visceral fat with increasing PM₂.₅, and the numbers of macrophages were even higher after than those during the Games. Moreover, the number of neutrophils was markedly higher in the spleen for the PM₂.₅-exposed- than the FA-group. These data suggest that short-term increases in exposure to ambient PM₂.₅ leads to increased systemic inflammatory responses, primarily macrophages and neutrophils in the lung, spleen, and visceral adipose tissue. Short-term air quality improvements were significantly associated with reduced overall inflammatory responses.