Masako Morishita

Insights Into the Mechanisms and Mediators of the Effects of Air Pollution Exposure on Blood Pressure and Vascular Function in Healthy Humans

Fine particulate matter air pollution plus ozone impairs vascular function and raises diastolic blood pressure. We aimed to determine the mechanism and air pollutant responsible. The effects of pollution on heart rate variability, blood pressure, biomarkers, and brachial flow-mediated dilatation were determined in 2 randomized, double-blind, crossover studies. In Ann Arbor, 50 subjects were exposed to fine particles (150 &mgr;g/m3) plus ozone (120 parts per billion) for 2 hours on 3 occasions with pretreatments of an endothelin antagonist (Bosentan, 250 mg), antioxidant (Vitamin C, 2 g), or placebo. In Toronto, 31 subjects were exposed to 4 different conditions (particles plus ozone, particles, ozone, and filtered air). In Toronto, diastolic blood pressure significantly increased (2.9 and 3.6 mm Hg) only during particle-containing exposures in association with particulate matter concentration and reductions in heart rate variability. Flow-mediated dilatation significantly decreased (2.0% and 2.9%) only 24 hours after particle-containing exposures in association with particulate matter concentration and increases in blood tumor necrosis factor &agr;. In Ann Arbor, diastolic blood pressure significantly similarly increased during all of the exposures (2.5 to 4.0 mm Hg), a response not mitigated by pretreatments. Flow-mediated dilatation remained unaltered. Particulate matter, not ozone, was responsible for increasing diastolic blood pressure during air pollution inhalation, most plausibly by instigating acute autonomic imbalance. Only particles from urban Toronto additionally impaired endothelial function, likely via slower proinflammatory pathways. Our findings demonstrate credible mechanisms whereby fine particulate matter could trigger acute cardiovascular events and that aspects of exposure location may be an important determinant of the health consequences.

Long-Term Exposure to Concentrated Ambient PM2.5 Increases Mouse Blood Pressure through Abnormal Activation of the Sympathetic Nervous System: A Role for Hypothalamic Inflammation

Background: Exposure to particulate matter ≤ 2.5 μm in diameter (PM2.5) increases blood pressure (BP) in humans and animal models. Abnormal activation of the sympathetic nervous system may have a role in the acute BP response to PM2.5 exposure. The mechanisms responsible for sympathetic nervous system activation and its role in chronic sustenance of hypertension in response to PM2.5 exposure are currently unknown. Objectives: We investigated whether central nervous system inflammation may be implicated in chronic PM2.5 exposure-induced increases in BP and sympathetic nervous system activation. Methods: C57BL/6J mice were exposed to concentrated ambient PM2.5 (CAPs) for 6 months, and we analyzed BP using radioactive telemetric transmitters. We assessed sympathetic tone by measuring low-frequency BP variability (LF-BPV) and urinary norepinephrine excretion. We also tested the effects of acute pharmacologic inhibitors of the sympathetic nervous system and parasympathetic nervous system. Results: Long-term CAPs exposure significantly increased basal BP, paralleled by increases in LF-BPV and urinary norepinephrine excretion. The increased basal BP was attenuated by the centrally acting α2a agonist guanfacine, suggesting a role of increased sympathetic tone in CAPs exposure–induced hypertension. The increase in sympathetic tone was accompanied by an inflammatory response in the arcuate nucleus of the hypothalamus, evidenced by increased expression of pro-inflammatory genes and inhibitor kappaB kinase (IKK)/nuclear factor–kappaB (NF-κB) pathway activation. Conclusion: Long-term CAPs exposure increases BP through sympathetic nervous system activation, which may involve hypothalamic inflammation. Citation: Ying Z, Xu X, Bai Y, Zhong J, Chen M, Liang Y, Zhao J, Liu D, Morishita M, Sun Q, Spino C, Brook RD, Harkema JR, Rajagopalan S. 2014. Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation. Environ Health Perspect 122:79–86; http://dx.doi.org/10.1289/ehp.1307151

Air pollution-mediated susceptibility to inflammation and insulin resistance: Influence of CCR2 pathways in mice

Background: Epidemiologic and experimental studies support an association between PM2.5 exposure and insulin resistance (IR). Innate immune cell activation has been suggested to play a role in the pathogenesis of these effects. Objectives: We sought to evaluate the role of CC-chemokine receptor 2 (CCR2) in PM2.5-mediated inflammation and IR. Methods: Wild-type C57BL/6 and CCR2–/– male mice were fed a high-fat diet and exposed to either concentrated ambient PM2.5 or filtered air for 17 weeks via a whole-body exposure system. We evaluated glucose tolerance and insulin sensitivity. At euthanasia, blood, spleen, and visceral adipose tissue (VAT) were collected, and inflammatory cells were measured using flow cytometry. We used standard immunoblots, immunohistochemical methods, and quantitative PCR (polymerase chain reaction) to assess pathways of interest involving insulin signaling, inflammation, and lipid and glucose metabolism in various organs. Vascular function was assessed using myography. Results: PM2.5 exposure resulted in whole-body IR and increased hepatic lipid accumulation in the liver, which was attenuated in CCR2–/– mice by inhibiting SREBP1c-mediated transcriptional programming, decreasing fatty acid uptake, and suppressing p38 MAPK activity. Abnormal phosphorylation levels of AKT, AMPK in VAT, and adipose tissue macrophage content in wild-type mice were not present in CCR2–/– mice. However, the impaired whole-body glucose tolerance and reduced GLUT-4 in skeletal muscle in response to PM2.5 was not corrected by CCR2 deficiency. Conclusions: PM2.5 mediates IR by regulating VAT inflammation, hepatic lipid metabolism, and glucose utilization in skeletal muscle via both CCR2-dependent and -independent pathways. These findings provide new mechanistic links between air pollution and metabolic abnormalities underlying IR. Citation: Liu C, Xu X, Bai Y, Wang TY, Rao X, Wang A, Sun L, Ying Z, Gushchina L, Maiseyeu A, Morishita M, Sun Q, Harkema JR, Rajagopalan S. 2014. Air pollution–mediated susceptibility to inflammation and insulin resistance: influence of CCR2 pathways in mice. Environ Health Perspect 122:17–26; http://dx.doi.org/10.1289/ehp.1306841

Pulmonary Retention of Particulate Matter is Associated with Airway Inflammation in Allergic Rats Exposed to Air Pollution in Urban Detroit

A collaborative research study was conducted in order to improve our understanding of the source-to-receptor pathway for ambient fine particulate matter (aerodynamic diameter ≤ 2.5 μ m; PM2.5) and subsequently to investigate the identity and sources of toxic components in PM2.5 responsible for adverse health effects in allergic humans. This research used a Harvard fine particle concentrator to expose Brown Norway rats, with and without ovalbumin-induced allergic airway disease, to concentrated air particles (CAPs) generated from ambient air in an urban Detroit community where the pediatric asthma rate was three times higher than the national average. Rats were exposed to CAPs during the exposure periods in July (mean = 676 μg/m3) and September (313 μg/m3) of 2000. Twenty-four hours after exposures lung lobes were either lavaged with saline to determine cellularity and protein in bronchoalveolar lavage fluid (BALF), or removed for analysis by inductively coupled plasma–mass spectrometry (ICP-MS) to detect ambient PM2.5-derived trace element retention. PM2.5 trace elements of anthropogenic origin, lanthanum (La), vanadium (V), manganese (Mn), and sulfur (S), were recovered from the lung tissues of CAPs-exposed rats. Recovery of those pulmonary anthropogenic particles was further increased in rats with allergic airways. In addition, eosinophils and protein in BALF were increased only in allergic animals exposed to CAPs. These results demonstrate preferential retention in allergic airways of air particulates derived from identified local combustion sources after a short-term exposure. Our findings suggest that the enhancement of allergic airway responses by exposure to PM2.5 is mediated in part by increased pulmonary deposition and localization of potentially toxic elements in urban air.

Cardiovascular depression in rats exposed to inhaled particulate matter and ozone: Effects of diet-induced metabolic syndrome

Background: High ambient levels of ozone (O3) and fine particulate matter (PM2.5) are associated with cardiovascular morbidity and mortality, especially in people with preexisting cardiopulmonary diseases. Enhanced susceptibility to the toxicity of air pollutants may include individuals with metabolic syndrome (MetS). Objective: We tested the hypothesis that cardiovascular responses to O3 and PM2.5 will be enhanced in rats with diet-induced MetS. Methods: Male Sprague-Dawley rats were fed a high-fructose diet (HFrD) to induce MetS and then exposed to O3, concentrated ambient PM2.5, or the combination of O3 plus PM2.5 for 9 days. Data related to heart rate (HR), HR variability (HRV), and blood pressure (BP) were collected. Results: Consistent with MetS, HFrD rats were hypertensive and insulin resistant, and had elevated fasting levels of blood glucose and triglycerides. Decreases in HR and BP, which were found in all exposure groups, were greater and more persistent in HFrD rats compared with those fed a normal diet (ND). Coexposure to O3 plus PM2.5 induced acute drops in HR and BP in all rats, but only ND rats adapted after 2 days. HFrD rats had little exposure-related changes in HRV, whereas ND rats had increased HRV during O3 exposure, modest decreases with PM2.5, and dramatic decreases during O3 plus PM2.5 coexposures. Conclusions: Cardiovascular depression in O3- and PM2.5-exposed rats was enhanced and prolonged in rats with HFrD-induced MetS. These results in rodents suggest that people with MetS may be prone to similar exaggerated BP and HR responses to inhaled air pollutants. Citation: Wagner JG, Allen K, Yang HY, Nan B, Morishita M, Mukherjee B, Dvonch JT, Spino C, Fink GD, Rajagopalan S, Sun Q, Brook RD, Harkema JR. 2014. Cardiovascular depression in rats exposed to inhaled particulate matter and ozone: effects of diet-induced metabolic syndrome. Environ Health Perspect 122:27–33; http://dx.doi.org/10.1289/ehp.1307085

Central IKKβ inhibition prevents air pollution mediated peripheral inflammation and exaggeration of type II diabetes

BackgroundPrior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 μm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus (Type II DM). We investigated the role of hypothalamic inflammation in PM2.5-mediated diabetes development.MethodsKKay mice, a genetically susceptible model of Type II DM, were assigned to either concentrated PM2.5 or filtered air (FA) for 4–8 weeks via a versatile aerosol concentrator and exposure system, or administered intra-cerebroventricular with either IKKβ inhibitor (IMD-0354) or TNFα antibody (infliximab) for 4–5 weeks simultaneously with PM2.5 exposure. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen, visceral adipose tissue and hypothalamus were collected to measure inflammatory cells using flow cytometry. Standard immunohistochemical methods and quantitative PCR were used to assess targets of interest.ResultsPM2.5 exposure led to hyperglycemia and insulin resistance, which was accompanied by increased hypothalamic IL-6, TNFα, and IKKβ mRNA expression and microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKβ inhibitor [IMD-0354, n = 8 for each group)], but not TNFα blockade with infliximab [(n = 6 for each group], improved glucose tolerance, insulin sensitivity, rectified energy homeostasis (O2 consumption, CO2 production, respiratory exchange ratio and heat generation) and reduced peripheral inflammation in response to PM2.5.ConclusionsCentral inhibition of IKKβ prevents PM2.5 mediated peripheral inflammation and exaggeration of type II diabetes. These results provide novel insights into how air pollution may mediate susceptibility to insulin resistance and Type II DM.

Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location

Background: Fine particulate matter (PM) air pollution is associated with numerous adverse health effects, including increased blood pressure (BP) and vascular dysfunction. Coarse PM substantially contributes to global air pollution, yet differs in characteristics from fine particles and is currently not regulated. However, the cardiovascular (CV) impacts of coarse PM exposure remain largely unknown. Objectives: Our goal was to elucidate whether coarse PM, like fine PM, is itself capable of eliciting adverse CV responses. Methods: We performed a randomized double-blind crossover study in which 32 healthy adults (25.9 ± 6.6 years of age) were exposed to concentrated ambient coarse particles (CAP; 76.2 ± 51.5 μg/m3) in a rural location and filtered air (FA) for 2 hr. We measured CV outcomes during, immediately after, and 2 hr postexposures. Results: Both systolic (mean difference = 0.32 mmHg; 95% CI: 0.05, 0.58; p = 0.021) and diastolic BP (0.27 mmHg; 95% CI: 0.003, 0.53; p = 0.05) linearly increased per 10 min of exposure during the inhalation of coarse CAP when compared with changes during FA exposure. Heart rate was on average higher (4.1 bpm; 95% CI: 3.06, 5.12; p < 0.0001) and the ratio of low-to-high frequency heart rate variability increased (0.24; 95% CI: 0.07, 0.41; p = 0.007) during coarse particle versus FA exposure. Other outcomes (brachial flow-mediated dilatation, microvascular reactive hyperemia index, aortic hemodynamics, pulse wave velocity) were not differentially altered by the exposures. Conclusions: Inhalation of coarse PM from a rural location is associated with a rapid elevation in BP and heart rate during exposure, likely due to the triggering of autonomic imbalance. These findings add mechanistic evidence supporting the biological plausibility that coarse particles could contribute to the triggering of acute CV events. Citation: Brook RD, Bard RL, Morishita M, Dvonch JT, Wang L, Yang HY, Spino C, Mukherjee B, Kaplan MJ, Yalavarthi S, Oral EA, Ajluni N, Sun Q, Brook JR, Harkema J, Rajagopalan S. 2014. Hemodynamic, autonomic, and vascular effects of exposure to coarse particulate matter air pollution from a rural location. Environ Health Perspect 122:624–630; http://dx.doi.org/10.1289/ehp.1306595

Effects of Concentrated Fine Ambient Particles on Rat Plasma Levels of Asymmetric Dimethylarginine

The health effects of ambient fine particulate matter (PM2.5) and its potential impact on vascular endothelial function have not been thoroughly investigated. As endothelial dysfunction plays an important role in the pathogenesis of atherosclerosis and its complications, we examined the effects of concentrated fine ambient particles (CAPs) on the plasma level of asymmetric dimethylarginine (ADMA) in a pilot study. ADMA is a circulating endogenous inhibitor of nitric oxide synthase (NOS) that is associated with impaired vascular function and increased risk for cardiovascular events. A mobile air research laboratory (AirCARE 1) was used to provide “real-world” CAPs exposures for this study conducted in Detroit, MI. Fourteen Brown Norway rats were exposed to filtered air (FA) (n = 7) or CAPs (0.1–2.5 μm) (n = 7) for 3 consecutive days (8 h/day) in July 2002. Rats were exposed during these periods to average particle mass concentrations of 354 μg/m3. Rat plasma samples were collected 24 h postexposure. Plasma concentrations of ADMA were significantly elevated in rats exposed to CAPs versus those exposed to FA (mean ± standard deviation = 1.49 ± 0.18 vs. 1.29 ± 0.26 μM, p = .05 by one-tailed t-test). Analyses of meteorological data and CAPs trace element composition suggest thatlocal particle emission sources contributed largely to overall mass of CAPs. Results of this pilot study suggest that exposure to PM2.5 at high concentrations may trigger an acute increase in circulating ADMA level. This finding has implications for the regulation of vasomotor tone by particulate pollutants and the propensity for adverse cardiovascular events.

Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome

Abstract Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100–400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

Evaluating porous-layer open-tubular capillaries as vapor preconcentrators in a microanalytical system

Abstract Measuring environmental concentrations of organic vapors with microfabricated chemical sensors or sensor arrays often requires a means to enrich collected samples prior to detection. With such an application in mind, a preliminary evaluation is described of two porous-layer open tubular (PLOT) capillary traps as vapor preconcentrators for a series of vapors. Short (1-cm) sections of commercial PLOT-Q and PLOT-S capillary having wall coatings of styrene–divinylbenzene copolymer and vinylpyridine–divinylbenzene copolymer, respectively, are fitted with a metal sleeve for rapid thermal desorption of preconcentrated vapor samples, and tested using a downstream 97-MHz polyisobutylene-coated surface acoustic wave (SAW) sensor. Calibrated responses to vapors of 2-butanone (MEK), trichloroethylene (TCE), toluene, and m -xylene are collected with and without preconcentration. Dimethylmethylphosphonate could not be efficiently desorbed from either PLOT trap. For the remaining vapors, increases in sensitivity of 3–9-fold are achieved by preconcentrating and analyzing just 1 ml of sample air. Calculated limits of detection (LOD) range from 1–8 ppm. Differences in sensitivities are observed between the PLOT-Q and PLOT-S sampling trains for MEK and TCE. A theoretical model of penetration yields limiting values of flow rate and trap dimensions. Measured 10%-breakthrough times at 1 ml/min ranged from ∼1 to 6 min and, for PLOT-Q, are ≥ modeled values obtained using the modified Wheeler equation. The implications of the results for the design and operation of microanalytical systems for vapor analytes are discussed.