Assessment of particulate matter toxicity and physicochemistry at the Claim 28 uranium mine site in Blue Gap, AZ.

Thousands of abandoned uranium mines (AUMs) exist in the western United States. Due to improper remediation, windblown dusts generated from AUMs are of significant community concern. A mobile inhalation lab was sited near an AUM of high community concern ("Claim 28") with three primary objectives: to (1) determine the composition of the regional ambient particulate matter (PM), (2) assess meteorological characteristics (wind speed and direction), and (3) assess immunological and physiological responses of mice after exposures to concentrated ambient PM (or CAPs). C57BL/6 and apolipoprotein E-null (ApoE-/-) mice were exposed to CAPs in AirCARE1 located approximately 1 km to the SW of Claim 28, for 1 or 28 days for 4 hr/day at approximately 80 µg/m3 CAPs. Bronchoalveolar lavage fluid (BALF) analysis revealed a significant influx of neutrophils after a single-day exposure in C57BL/6 mice (average PM2.5 concentration = 68 µg/m3). Lungs from mice exposed for 1 day exhibited modest increases in Tnfa and Tgfb mRNA levels in the CAPs exposure group compared to filtered air (FA). Lungs from mice exposed for 28 days exhibited reduced Tgfb (C57BL/6) and Tnfa (ApoE-/-) mRNA levels. Wind direction was typically moving from SW to NE (away from the community) and, while detectable in all samples, uranium concentrations in the PM2.5 fraction were not markedly different from published-reported values. Overall, exposure to CAPs in the region of the Blue GAP Tachee's Claim-28 uranium mine demonstrated little evidence of overt pulmonary injury or inflammation or ambient air contamination attributed to uranium or vanadium.

Neighborhood air pollution and household environmental health as it relates to respiratory health and healthcare utilization among elderly persons with asthma.

Objective: The study investigated the associations between fine particulate matter (PM2.5; <2.5 µm in diameter), indoor environment, pulmonary function, and healthcare utilization in a vulnerable group of elderly persons with asthma. We hypothesized that environmental conditions were associated with adverse pulmonary health outcomes. Methods: The study involved elderly (n = 76; mean age 64.6 years; 48 women) vulnerable persons in Detroit, Michigan, USA, with physician-diagnosed asthma. Exposure variables included measured outdoor PM2.5, self-rated outdoor and household environmental pollutants. Outcome variables were self-rated and measured pulmonary function, and asthma-related healthcare utilization. Results: Mean ambient PM2.5 concentrations during the study was 14.14 ± (S.D. 6.36) µg/m3 during the summer and 14.20 (6.33) during the winter (p = 0.95). In multiple regression analyses, adjusting for age and gender, mean 6-month concentration of PM2.5 was related to shortness of breath (SHOB; standardized ß = 0.26, p = 0.02) and inversely with self-rated respiratory health (SRRH; ß = 0.28, p = 0.02). However, PM2.5 did not predict lung function (FEV1% predicted and FEV1/FVC). However, PM2.5 was related to use of asthma controller drugs (ß = 0.38, p = 0.001). Participants' air pollution ratings predicted total healthcare utilization (ß = 0.33, p = 0.01). Conclusions: In elderly persons with asthma, living near heavy industry and busy highways, objective and perceived environmental pollution relate to participants' respiratory health and healthcare utilization. Importantly, air pollution might increase use of asthma controller drugs containing corticosteroids with implication for elderly persons' risk to develop osteoporosis and cardiovascular disease.

Serum-borne factors alter cerebrovascular endothelial microRNA expression following particulate matter exposure near an abandoned uranium mine on the Navajo Nation.

BACKGROUND: Commercial uranium mining on the Navajo Nation has subjected communities on tribal lands in the Southwestern United States to exposures from residual environmental contamination. Vascular health effects from these ongoing exposures are an active area of study. There is an association between residential mine-site proximity and circulating biomarkers in residents, however, the contribution of mine-site derived wind-blown dusts on vascular and other health outcomes is unknown. To assess neurovascular effects of mine-site derived dusts, we exposed mice using a novel exposure paradigm, the AirCARE1 mobile inhalation laboratory, located 2 km from an abandoned uranium mine, Claim 28 in Blue Gap Tachee, AZ. Mice were exposed to filtered air (FA) (n = 6) or concentrated ambient particulate matter (CAPs) (n = 5) for 2 wks for 4 h per day. RESULTS: To assess miRNA differential expression in cultured mouse cerebrovascular cells following particulate matter (PM) exposure (average: 96.6 ± 60.4 µg/m3 for all 4 h exposures), the serum cumulative inflammatory potential (SCIP) assay was employed. MiRNA sequencing was then performed in cultured mouse cerebrovascular endothelial cells (mCECs) to evaluate transcriptional changes. Results indicated 27 highly differentially expressed (p < 0.01) murine miRNAs, as measured in the SCIP assay. Gene ontology (GO) pathway analysis revealed notable alterations in GO enrichment related to the cytoplasm, protein binding and the cytosol, while significant KEGG pathways involved pathways in cancer, axon guidance and Wnt signaling. Expression of these 27 identified, differentially expressed murine miRNAs were then evaluated in the serum. Nine of these miRNAs (~ 30%) were significantly altered in the serum and 8 of those miRNAs demonstrated the same directional change (either upregulation or downregulation) as cellular miRNAs, as measured in the SCIP assay. Significantly upregulated miRNAs in the CAPs exposure group included miRNAs in the let-7a family. Overexpression of mmu-let-7a via transfection experiments, suggested that this miRNA may mediate mCEC barrier integrity following dust exposure. CONCLUSIONS: Our data suggest that mCEC miRNAs as measured in the SCIP assay show similarity to serum-borne miRNAs, as approximately 30% of highly differentially expressed cellular miRNAs in the SCIP assay were also found in the serum. While translocation of miRNAs via exosomes or an alternative mechanism is certainly possible, other yet-to-be-identified factors in the serum may be responsible for significant miRNA differential expression in endothelium following inhaled exposures. Additionally, the most highly upregulated murine miRNAs in the CAPs exposure group were in the let-7a family. These miRNAs play a prominent role in cell growth and differentiation and based on our transfection experiments, mmu-let-7a may contribute to cerebrovascular mCEC alterations following inhaled dust exposure.

In vivo biodistribution and physiologically based pharmacokinetic modeling of inhaled fresh and aged cerium oxide nanoparticles in rats.

BACKGROUND: Cerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation. Therefore, understanding the pharmacokinetic of newly-generated and atmospherically-aged CeO2 nanoparticles is needed to assess the risks to human health. METHODS: A novel experimental system was designed to integrate the generation, aging, and inhalation exposure of Sprague Dawley rats to combustion-generated CeO2 nanoparticles (25 and 90 nm bimodal distribution). Aging was done in a chamber representing typical ambient urban air conditions with UV lights. Following a single 4-hour nose-only exposure to freshly emitted or aged CeO2 for 15 min, 24 h, and 7 days, ICP-MS detection of Ce in the blood, lungs, gastrointestinal tract, liver, spleen, kidneys, heart, brain, olfactory bulb, urine, and feces were analyzed with a mass balance approach to gain an overarching understanding of the distribution. A physiologically based pharmacokinetic (PBPK) model that includes mucociliary clearance, phagocytosis, and entry into the systemic circulation by alveolar wall penetration was developed to predict the biodistribution kinetic of the inhaled CeO2 nanoparticles. RESULTS: Cerium was predominantly recovered in the lungs and feces, with extrapulmonary organs contributing less than 4 % to the recovery rate at 24 h post exposure. No significant differences in biodistribution patterns were found between fresh and aged CeO2 nanoparticles. The PBPK model predicted the biodistribution well and identified phagocytizing cells in the pulmonary region accountable for most of the nanoparticles not eliminated by feces. CONCLUSIONS: The biodistribution of fresh and aged CeO2 nanoparticles followed the same patterns, with the highest amounts recovered in the feces and lungs. The slow decrease of nanoparticle concentrations in the lungs can be explained by clearance to the gastrointestinal tract and then to the feces. The PBPK model successfully predicted the kinetic of CeO2 nanoparticles in various organs measured in this study and suggested most of the nanoparticles were captured by phagocytizing cells.

Exposure to concentrated ambient particulate matter induces reversible increase of heart weight in spontaneously hypertensive rats.

BACKGROUND: Exposure to ambient PM2.5 increases cardiovascular mortality and morbidity. To delineate the underlying biological mechanism, we investigated the time dependence of cardiovascular response to chronic exposure to concentrated ambient PM2.5 (CAP). METHODS: Spontaneously hypertensive rats (SHR) were exposed to CAP for 15 weeks, and blood pressure (BP), cardiac function and structure, and inflammations of lung, hypothalamus, and heart were measured at different time points. RESULTS: Chronic exposure to CAP significantly increased BP, and withdrawal from CAP exposure restored BP. Consistent with its BP effect, chronic exposure to CAP significantly decreased cardiac stroke volume and output in SHR, accompanied by increased heart weight and increased cardiac expression of hypertrophic markers ACTA1 and MYH7. Withdrawal from CAP exposure restored cardiac function, weight, and expression of hypertrophic markers, supporting the notion that cardiac dysfunction and hypertrophy is subsequent to hypertension. In agreement with the role of systemic inflammation in mediating the cardiovascular effects of CAP exposure, chronic exposure to CAP markedly increased expression of pro-inflammatory cytokines in lung, heart, and hypothalamus. However, withdrawal from exposure resolves inflammation in the heart and hypothalamus, but not in the lung, suggesting that CAP exposure-induced systemic inflammation may be independent of pulmonary inflammation. CONCLUSION: Chronic exposure to CAP induces reversible cardiac dysfunction and hypertrophy, which is likely to be subsequent to the elevation in BP and induction of systemic inflammation as evidenced by increased mRNA expression of pro-inflammatory cytokines in diverse tissues.

PM2.5-induced cardiovascular dysregulation in rats is associated with elemental carbon and temperature-resolved carbon subfractions.

BACKGROUND: We tested the hypothesis that cardiovascular responses to PM2.5 exposure will be enhanced in hypertensive rats and linked to specific carbonaceous pollutants in an urban industrial setting. METHODS: Spontaneously hypertensive rats were exposed by inhalation to concentrated PM2.5 in an industrial area of Dearborn, Michigan, for four consecutive summer days. Blood pressure (BP), heart rate (HR) and HR variability (HRV) metrics (SDNN, RMSSD) were assessed by radiotelemetry and compared to 1 h- and 8 h-averaged fluctuations in PM2.5 composition, with a focus on elemental and organic carbon (EC and OC, respectively), and temperature-resolved subfractions (EC1-EC5, PC (pyrolized carbon), and OC1-OC4), as well as other major and minor PM components. RESULTS: Mean HR and BP were increased, while HRV was decreased over 4 days of exposure. Using 1 h averages, EC (1 µg/m3 increase) was associated with increased HR of 11-32 bpm (4-11% increase), 1.2-1.5 ms (22-27%) decreases in SDNN, 3-14 mmHg (1.5-8%) increases in systolic BP, and 5-12 mmHg (4-9%) increases in diastolic BP. By comparison, associations with OC were negligible. Using 8 h averages, EC subfractions were linked with increased heart rate (EC1: 13 bpm; EC2, EC3, PC: <5 bpm) and SDNN (EC1> > EC2 > EC3, EC4, PC), but with decreased RMSSD (EC2, EC5 > EC3, EC4). Minimal effects were associated with OC and OC1. Associations between carbon subfractions and BP were negligible. Associations with non-carbonaceous components and trace elements were generally non-significant or of negligible effect size. CONCLUSIONS: These findings are the first to describe associations between acute cardiovascular responses and thermally resolved carbon subfractions. We report that cardiovascular responses to PM2.5 carbonaceous materials appear to be driven by EC and its EC1 fraction.

Exaggerated effects of particulate matter air pollution in genetic type II diabetes mellitus.

BACKGROUND: Prior 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. This study was designed to investigate whether inhalational exposure of concentrated PM2.5 in a genetically susceptible animal model would result in abnormalities in energy metabolism and exacerbation of peripheral glycemic control. METHODS: KKay mice, which are susceptible to Type II DM, were assigned to either concentrated ambient PM2.5 or filtered air (FA) for 5-8 weeks via a whole body exposure system. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen and visceral adipose tissue were collected to measure inflammatory cells using flow cytometry. Standard immnunohistochemical methods, western blotting and quantitative PCR were used to assess targets of interest. RESULTS: PM2.5 exposure influenced energy metabolism including O2 consumption, CO2 production, respiratory exchange ratio and thermogenesis. These changes were accompanied by worsened insulin resistance, visceral adiposity and inflammation in spleen and visceral adipose depots. Plasma adiponectin were decreased in response to PM2.5 exposure while leptin levels increased. PM2.5 exposure resulted in a significant increase in expression of inflammatory genes and decreased UCP1 expression in brown adipose tissue and activated p38 and ERK pathways in the liver of the KKay mice. CONCLUSIONS: Concentrated ambient PM2.5 exposure impairs energy metabolism, concomitant with abnormalities in glucose homeostasis, increased inflammation in insulin responsive organs, brown adipose inflammation and results in imbalance in circulating leptin/adiponectin levels in a genetically susceptible diabetic model. These results provide additional insights into the mechanisms surrounding air pollution mediated susceptibility to Type II DM.

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

BACKGROUND: Prior 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. METHODS: KKay 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 IKKß 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. RESULTS: PM2.5 exposure led to hyperglycemia and insulin resistance, which was accompanied by increased hypothalamic IL-6, TNFα, and IKKß mRNA expression and microglial/astrocyte reactivity. Targeting the NFκB pathway with intra-cerebroventricular administration of an IKKß 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. CONCLUSIONS: Central inhibition of IKKß 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.

No effect of acute exposure to coarse particulate matter air pollution in a rural location on high-density lipoprotein function.

CONTEXT: High-density lipoprotein (HDL) particles perform numerous vascular-protective functions. Animal studies demonstrate that exposure to fine or ultrafine particulate matter (PM) can promote HDL dysfunction. However, the impact of PM on humans remains unknown. OBJECTIVE: We aimed to determine the effect of exposure to coarse concentrated ambient particles (CAP) on several metrics of HDL function in healthy humans. METHODS: Thirty-two adults (25.9 ± 6.6 years) were exposed to coarse CAP [76.2 ± 51.5 µg·m(-3)] in a rural location and filtered air (FA) for 2 h in a randomized double-blind crossover study. Venous blood collected 2- and 20-h post-exposures was measured for HDL-mediated efflux of [(3)H]-cholesterol from cells and 20-h exposures for HDL anti-oxidant capacity by a fluorescent assay and paraoxonase activity. The changes [median (first, third quartiles)] between exposures among 29 subjects with available results were compared by matched Wilcoxon tests. RESULTS: HDL-mediated cholesterol efflux capacity did not differ between exposures at either time point [16.60% (15.17, 19.19) 2-h post-CAP versus 17.56% (13.43, 20.98) post-FA, p = 0.768 and 14.90% (12.47, 19.15) 20-h post-CAP versus 17.75% (13.22, 23.95) post-FA, p = 0.216]. HOI [0.26 (0.24, 0.35) versus 0.28 (0.25, 0.40), p = 0.198] and paraoxonase activity [0.54 (0.39, 0.82) versus 0.60 µmol·min(-1 )ml plasma(-1) (0.40, 0.85), p = 0.137] did not differ 20-h post-CAP versus FA, respectively. CONCLUSIONS: Brief inhalation of coarse PM from a rural location did not acutely impair several facets of HDL functionality. Whether coarse PM derived from urban sites, fine particles or longer term PM exposures can promote HDL dysfunction warrant future investigations.

Ambient fine particulate matter and ozone exposures induce inflammation in epicardial and perirenal adipose tissues in rats fed a high fructose diet.

BACKGROUND: Inflammation and oxidative stress play critical roles in the pathogenesis of inhaled air pollutant-mediated metabolic disease. Inflammation in the adipose tissues niches are widely believed to exert important effects on organ dysfunction. Recent data from both human and animal models suggest a role for inflammation and oxidative stress in epicardial adipose tissue (EAT) as a risk factor for the development of cardiovascular disease. We hypothesized that inhalational exposure to concentrated ambient fine particulates (CAPs) and ozone (O3) exaggerates inflammation and oxidative stress in EAT and perirenal adipose tissue (PAT). METHODS: Eight- week-old Male Sprague-Dawley rats were fed a normal diet (ND) or high fructose diet (HFr) for 8 weeks, and then exposed to ambient AIR, CAPs at a mean of 356 µg/m3, O3 at 0.485 ppm, or CAPs (441 µg/m3) + O3 (0.497 ppm) in Dearborn, MI, 8 hours/day, 5 days/week, for 9 days over 2 weeks. RESULTS: EAT and PAT showed whitish color in gross, and less mitochondria, higher mRNA expression of white adipose specific and lower brown adipose specific genes than in brown adipose tissues. Exposure to CAPs and O3 resulted in the increase of macrophage infiltration in both EAT and PAT of HFr groups. Proinflammatory genes of Tnf-α, Mcp-1 and leptin were significantly upregulated while IL-10 and adiponectin, known as antiinflammatory genes, were reduced after the exposures. CAPs and O3 exposures also induced an increase in inducible nitric oxide synthase (iNOS) protein expression, and decrease in mitochondrial area in EAT and PAT. We also found significant increases in macrophages of HFr-O3 rats. The synergetic interaction of HFr and dirty air exposure on the inflammation was found in most of the experiments. Surprisingly, exposure to CAPs or O3 induced more significant inflammation and oxidative stress than co-exposure of CAPs and O3 in EAT and PAT. CONCLUSION: EAT and PAT are both white adipose tissues. Short-term exposure to CAPs and O3, especially with high fructose diet, induced inflammation and oxidative stress in EAT and PAT in rats. These findings may provide a link between air-pollution exposure and accelerated susceptibility to cardiovascular disease and metabolic complications.

The effect of acute exposure to coarse particulate matter air pollution in a rural location on circulating endothelial progenitor cells: results from a randomized controlled study.

CONTEXT: Fine particulate matter (PM) air pollution has been associated with alterations in circulating endothelial progenitor cell (EPC) levels, which may be one mechanism whereby exposures promote cardiovascular diseases. However, the impact of coarse PM on EPCs is unknown. OBJECTIVE: We aimed to determine the effect of acute exposure to coarse concentrated ambient particles (CAP) on circulating EPC levels. METHODS: Thirty-two adults (25.9 ± 6.6 years) were exposed to coarse CAP (76.2 ± 51.5 µg m(-3)) in a rural location and filtered air (FA) for 2 h in a randomized double-blind crossover study. Peripheral venous blood was collected 2 and 20 h post-exposures for circulating EPC (n = 21), white blood cell (n = 24) and vascular endothelial growth factor (VEGF) (n = 16-19) levels. The changes between exposures were compared by matched Wilcoxon signed-rank tests. RESULTS: Circulating EPC levels were elevated 2 [108.29 (6.24-249.71) EPC mL(-1); median (25th-75th percentiles), p = 0.052] and 20 h [106.86 (52.91-278.35) EPC mL(-1), p = 0.008] post-CAP exposure compared to the same time points following FA [38.47 (0.00-84.83) and 50.16 (0.00-104.79) EPC mL(-1)]. VEGF and white blood cell (WBC) levels did not differ between exposures. CONCLUSIONS: Brief inhalation of coarse PM from a rural location elicited an increase in EPCs that persisted for at least 20 h. The underlying mechanism responsible may reflect a systemic reaction to an acute "endothelial injury" and/or a circulating EPC response to sympathetic nervous system activation.

Reduction of Outdoor and Indoor PM2.5 Source Contributions via Portable Air Filtration Systems in a Senior Residential Facility in Detroit, Michigan.

Background: The Reducing Air Pollution in Detroit Intervention Study (RAPIDS) was designed to evaluate cardiovascular health benefits and personal fine particulate matter (particulate matter < 2.5 µm in diameter, PM2.5) exposure reductions via portable air filtration units (PAFs) among older adults in Detroit, Michigan. This double-blind randomized crossover intervention study has shown that, compared to sham, air filtration for 3 days decreased 3-day average brachial systolic blood pressure by 3.2 mmHg. The results also showed that commercially available HEPA-type and true HEPA PAFs mitigated median indoor PM2.5 concentrations by 58% and 65%, respectively. However, to our knowledge, no health intervention study in which a significant positive health effect was observed has also evaluated how outdoor and indoor PM2.5 sources impacted the subjects. With that in mind, detailed characterization of outdoor and indoor PM2.5 samples collected during this study and a source apportionment analysis of those samples using a positive matrix factorization model were completed. The aims of this most recent work were to characterize the indoor and outdoor sources of the PM2.5 this community was exposed to and to assess how effectively commercially available HEPA-type and true HEPA PAFs were able to reduce indoor and outdoor PM2.5 source contributions. Methods: Approximately 24 h daily indoor and outdoor PM2.5 samples were collected on Teflon and Quartz filters from the apartments of 40 study subjects during each 3-day intervention period. These filters were analyzed for mass, carbon, and trace elements. Environmental Protection Agency Positive Matrix Factorization (PMF) 5.0 was utilized to determine major emission sources that contributed to the outdoor and indoor PM2.5 levels during this study. Results: The major sources of outdoor PM2.5 were secondary aerosols (28%), traffic/urban dust (24%), iron/steel industries (15%), sewage/municipal incineration (10%), and oil combustion/refinery (6%). The major sources of indoor PM2.5 were organic compounds (45%), traffic + sewage/municipal incineration (14%), secondary aerosols (13%), smoking (7%), and urban dust (2%). Infiltration of outdoor PM2.5 for sham, HEPA-type, and true HEPA air filtration was 79 ± 24%, 61 ± 32%, and 51 ± 34%, respectively. Conclusions: The results from our study showed that intervention with PAFs was able to significantly decrease indoor PM2.5 derived from outdoor and indoor PM2.5 sources. The PAFs were also able to significantly reduce the infiltration of outdoor PM2.5. The results of this study provide insights into what types of major PM2.5 sources this community is exposed to and what degree of air quality and systolic blood pressure improvements are possible through the use of commercially available PAFs in a real-world setting.

Divergent effects of urban particulate air pollution on allergic airway responses in experimental asthma: a comparison of field exposure studies.

BACKGROUND: Increases in ambient particulate matter of aerodynamic diameter of 2.5 µm (PM2.5) are associated with asthma morbidity and mortality. The overall objective of this study was to test the hypothesis that PM2.5 derived from two distinct urban U.S. communities would induce variable responses to aggravate airway symptoms during experimental asthma. METHODS: We used a mobile laboratory to conduct community-based inhalation exposures to laboratory rats with ovalbumin-induced allergic airways disease. In Grand Rapids exposures were conducted within 60 m of a major roadway, whereas the Detroit was located in an industrial area more than 400 m from roadways. Immediately after nasal allergen challenge, Brown Norway rats were exposed by whole body inhalation to either concentrated air particles (CAPs) or filtered air for 8 h (7:00 AM - 3:00 PM). Both ambient and concentrated PM2.5 was assessed for mass, size fractionation, and major component analyses, and trace element content. Sixteen hours after exposures, bronchoalveolar lavage fluid (BALF) and lung lobes were collected and evaluated for airway inflammatory and mucus responses. RESULTS: Similar CAPs mass concentrations were generated in Detroit (542 µg/m3) and Grand Rapids (519 µg/m3). Exposure to CAPs at either site had no effects in lungs of non-allergic rats. In contrast, asthmatic rats had 200% increases in airway mucus and had more BALF neutrophils (250% increase), eosinophils (90%), and total protein (300%) compared to controls. Exposure to Detroit CAPs enhanced all allergic inflammatory endpoints by 30-100%, whereas inhalation of Grand Rapids CAPs suppressed all allergic responses by 50%. Detroit CAPs were characterized by high sulfate, smaller sized particles and were derived from local combustion sources. Conversely Grand Rapids CAPs were derived primarily from motor vehicle sources. CONCLUSIONS: Despite inhalation exposure to the same mass concentration of urban PM2.5, disparate health effects can be elicited in the airways of sensitive populations such as asthmatics. Modulation of airway inflammatory and immune responses is therefore dependent on specific chemical components and size distributions of urban PM2.5. Our results suggest that air quality standards based on particle speciation and sources may be more relevant than particle mass to protect human health from PM exposure.

Neuroinflammatory and Neurometabolomic Consequences From Inhaled Wildfire Smoke-Derived Particulate Matter in the Western United States.

Utilizing a mobile laboratory located >300 km away from wildfire smoke (WFS) sources, this study examined the systemic immune response profile, with a focus on neuroinflammatory and neurometabolomic consequences, resulting from inhalation exposure to naturally occurring wildfires in California, Arizona, and Washington in 2020. After a 20-day (4 h/day) exposure period in a mobile laboratory stationed in New Mexico, WFS-derived particulate matter (WFPM) inhalation resulted in significant neuroinflammation while immune activity in the peripheral (lung, bone marrow) appeared to be resolved in C57BL/6 mice. Importantly, WFPM exposure increased cerebrovascular endothelial cell activation and expression of adhesion molecules (VCAM-1 and ICAM-1) in addition to increased glial activation and peripheral immune cell infiltration into the brain. Flow cytometry analysis revealed proinflammatory phenotypes of microglia and peripheral immune subsets in the brain of WFPM-exposed mice. Interestingly, endothelial cell neuroimmune activity was differentially associated with levels of PECAM-1 expression, suggesting that subsets of cerebrovascular endothelial cells were transitioning to resolution of inflammation following the 20-day exposure. Neurometabolites related to protection against aging, such as NAD+ and taurine, were decreased by WFPM exposure. Additionally, increased pathological amyloid-beta protein accumulation, a hallmark of neurodegeneration, was observed. Neuroinflammation, together with decreased levels of key neurometabolites, reflect a cluster of outcomes with important implications in priming inflammaging and aging-related neurodegenerative phenotypes.

PM2.5-induced changes in cardiac function of hypertensive rats depend on wind direction and specific sources in Steubenville, Ohio.

BACKGROUND: Increases in particulate matter less than 2.5 µm (PM(2.5)) in ambient air is linked to acute cardiovascular morbidity and mortality. Specific components and potential emission sources of PM(2.5) responsible for adverse health effects of cardiovascular function are unclear. METHODS: Spontaneously hypertensive rats were implemented with radiotelemeters to record ECG responses during inhalation exposure to concentrated ambient particles (CAPs) for 13 consecutive days in Steubenville, OH. Changes in heart rate (HR) and its variability (HRV) were compared to PM(2.5) trace elements in 30-min time frames to capture acute physiological responses with real-time fluctuations in PM(2.5) composition. Using positive matrix factorization, six major source factors were identified: (i) coal/secondary, (ii) mobile sources, (iii) metal coating/processing, (iv) iron/steel manufacturing, (v) lead and (vi) incineration. RESULTS: Exposure-related changes in HR and HRV were dependant on winds predominately from either the northeast (NE) or southwest (SW). During SW winds, the metal processing factor was associated with increased HR, whereas factors of incineration, lead and iron/steel with NE winds were associated with decreased HR. Decreased SDNN was dominated during NE winds by the incinerator factor, and with SW winds by the metal factor. Metals and mobile source factors also had minor impacts on decreased SDNN with NE winds. Individual elemental components loaded onto these factors generally showed significant associations, although there were some discrepancies. CONCLUSIONS: Acute cardiovascular changes in response to ambient PM(2.5) exposure can be attributed to specific PM constituents and sources linked with incineration, metal processing, and iron/steel production.

Cardiopulmonary responses in spontaneously hypertensive and Wistar-Kyoto rats exposed to concentrated ambient particles from Detroit, Michigan.

Toxicological effects have been observed in rats exposed to concentrated ambient particles (CAPs) from different regions of the United States. The objective of this study was to evaluate the cardiopulmonary and systemic effects of CAPs in Detroit. The authors stationed a mobile concentrator at a location near major traffic and industrial sources. Spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats were exposed to fine CAPs (diameter < 0.1-2.5 microm) 8 h/day for 13 consecutive days. Animals were implanted with telemeters, and electrocardiogram data were recorded continuously. Bronchoalveolar lavage (BAL) fluid and plasma were analyzed. Comprehensive exposure monitoring was conducted, including CAPs components. CAPs exposure concentrations were 103-918 microg/m(3) (mean = 502 microg/m(3)). The authors found no statistically significant differences in heart rate or SDNN (standard deviation of the normal-to-normal intervals), a measure of heart rate variability, between CAPs-exposed and control rats. The authors found significantly higher levels of C-reactive protein in the serum of CAPs-exposed SH rats compared with air-exposed animals. Protein in BAL fluid was elevated in WKY rats exposed to CAPs. Measurement of trace metals in lung tissue showed elevated concentrations of V, Sb, La, and Ce in CAPs-exposed SH animals versus controls. These elements are generally associated with oil combustion, oil refining, waste incineration, and traffic. Examination of wind rose data from the exposure period confirmed that the predominant wind direction was SSW, the direction of many of the aforementioned sources. These results indicate that ambient particles in Detroit can cause mild pulmonary and systemic changes in rats, and suggest the importance of local PM(2.5) sources in these effects.

Reduced Fine Particulate Matter Air Pollution Exposures Using In-Home Portable Air Cleaners: PILOT RESULTS OF THE CARDIAC REHABILITATION AIR FILTER TRIAL (CRAFT).

PURPOSE: Fine particulate matter (PM2.5) air pollution is a leading risk factor for cardiovascular disease. Even low levels common to millions of Americans pose health risks. However, no study has tested protective measures such as in-home portable air cleaners (PACs) among at-risk cardiac patients. We conducted a pilot phase of the Cardiac Rehabilitation Air Filter Trial (CRAFT)-a randomized, double-blind, crossover study of outpatient cardiac rehabilitation patients at Michigan Medicine. METHODS: During a routine visit, patients were provided with 2 PACs to run continuously for 5 d in both the bedroom and the main living space. PACs were randomized as active (with HEPA filter) versus sham. On day 4, subjects wore a personal PM2.5 monitor for 24-hr without activity restrictions. After a 1-wk washout, patients crossed over to the opposite mode. RESULTS: Patients (n = 20; 4 women) were elderly (70.8 ± 9.6 yr) nonsmokers with cardiovascular disease living near the facility (10.7 ± 6.0 mi). Compared with sham, active in-home PAC use significantly lowered personal-level 24-hr PM2.5 exposures by 43.8% (-12.2 µg·m; 95% CI, -24.2 to -0.2). Sensitivity analyses corroborated the reductions in most patients. CONCLUSION: An inexpensive in-home PAC can effectively lower personal PM2.5 exposures in cardiac patients. These benefits occurred even in a region with overall good air quality and if maintained over the long-term could translate into major reductions in cardiovascular events.

Neonatal Lead (Pb) Exposure and DNA Methylation Profiles in Dried Bloodspots.

Lead (Pb) exposure remains a major concern in the United States (US) and around the world, even following the removal of Pb from gasoline and other products. Environmental Pb exposures from aging infrastructure and housing stock are of particular concern to pregnant women, children, and other vulnerable populations. Exposures during sensitive periods of development are known to influence epigenetic modifications which are thought to be one mechanism of the Developmental Origins of Health and Disease (DOHaD) paradigm. To gain insights into early life Pb exposure-induced health risks, we leveraged neonatal dried bloodspots in a cohort of children from Michigan, US to examine associations between blood Pb levels and concomitant DNA methylation profiles (n = 96). DNA methylation analysis was conducted via the Infinium MethylationEPIC array and Pb levels were assessed via high resolution inductively coupled plasma mass spectrometry (HR-ICP-MS). While at-birth Pb exposure levels were relatively low (average 0.78 µg/dL, maximum of 5.27 ug/dL), we identified associations between DNA methylation and Pb at 33 CpG sites, with the majority (82%) exhibiting reduced methylation with increasing Pb exposure (q < 0.2). Biological pathways related to development and neurological function were enriched amongst top differentially methylated genes by p-value. In addition to increases/decreases in methylation, we also demonstrate that Pb exposure is related to increased variability in DNA methylation at 16 CpG sites. More work is needed to assess the accuracy and precision of metals assessment using bloodspots, but this study highlights the utility of this unique resource to enhance environmental epigenetics research around the world.

Effects of concentrated ambient particles and diesel engine exhaust on allergic airway disease in Brown Norway rats.

Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthmatic patients. Emissions from local stationary combustion sources (e.g., coal-burning power plants) or mobile motor vehicles (e.g., diesel-powered trucks) have been identified as potential contributors to the development or exacerbation of allergic airway disease. In the present study, a rodent model of allergic airway disease was used to study the effects of concentrated ambient particles (CAPs) or diesel engine exhaust (DEE) on the development of allergic airway disease in rats sensitized to the allergen ovalbumin (OVA). The overall objective of our project was to understand the effects of PM2.5 on the development of OVA-induced allergic airway disease. Our specific aims were to test the following hypotheses: (1) exposure to CAPs during OVA challenge enhances epithelial remodeling of the airway and inflammation in rats previously sensitized to the allergen; and (2) exposure to DEE during OVA sensitization, or during OVA challenge, exacerbates epithelial remodeling of the airway and inflammation in rats. In the DEE studies, Brown Norway (BN) rats were sensitized with three daily intranasal (IN) instillations of 0.5% OVA, and then two weeks later were challenged with IN OVA or saline for 3 consecutive days. Rats were exposed to DEE diluted to mass concentrations of 30 or 300 microg/m3 diesel exhaust particles (DEPs) or to filtered air during either the sensitization or challenge periods. For the CAPs studies, the same OVA sensitization and challenge rat model was used but exposures to Detroit, Michigan, CAPs were limited to the OVA challenge period. Two separate 3-day CAPs exposures were conducted (week 1, high mean mass concentration = 595 microg/m3; week 2, low mean mass concentration = 356 microg/m3) during OVA challenge. In both the DEE and CAPs studies, rats were killed 24 hours after the last OVA challenge, bronchoalveolar lavage fluid (BALF) was collected and analyzed for cellularity and secreted mediators, and lungs and nose were processed for histopathologic examination and morphometric analysis of intraepithelial mucosubstances (IM). The results of our animal inhalation studies in the southwest (SW) Detroit community, an area with elevated ambient PM2.5 concentrations, suggested that, during allergen challenge, exposure to CAPs that were predominantly associated with emissions from combustion sources markedly enhanced the OVA-induced allergic airway disease, which was characterized by an increased infiltration in the lungs of eosinophilic and lymphocytic inflammation, increased IM in conducting airways, and increased concentrations in BALF of mucin-specific proteins and inflammatory cytokines. These findings suggest that urban airborne PM2.5 derived from stationary combustion sources (e.g., refineries, coal-burning power plants, waste-treatment plants) may enhance the development of human allergic airway diseases like childhood asthma. Previous animal inhalation studies in this community have also suggested that these fine, ambient combustion-derived particles may also exacerbate preexisting allergic airway disease. In contrast to our CAPs studies in Detroit, the controlled DEE exposures of allergen-sensitized BN rats, during either allergen sensitization or challenge periods, caused only a few mild modifications in the character of the allergen-induced disease. This finding contrasts with other reported studies that indicate that DEPs at relatively higher exposure doses do enhance allergic airway disease in some rodent models. The reasons for these disparities between studies likely reflect differences in exposure dose, animal models, the timing of exposures to the allergens and DEP exposures, the methods of allergen sensitization and challenge, or physicochemical differences among DEEs.

Acute Blood Pressure and Cardiovascular Effects of Near-Roadway Exposures With and Without N95 Respirators.

BACKGROUND: The risk for cardiovascular events increases within hours of near-roadway exposures. We aimed to determine the traffic-related air pollution (TRAP) and biological mechanisms involved and if reducing particulate matter <2.5 µm (PM2.5) inhalation is protective. METHODS: Fifty healthy-adults underwent multiple 2-hour near-roadway exposures (Tuesdays to Fridays) in Ann Arbor during 2 separate weeks (randomized to wear an N95 respirator during 1 week). Monday both weeks, participants rested 2 hours in an exam room (once wearing an N95 respirator). Brachial blood pressure, aortic hemodynamics, and heart rate variability were repeatedly measured during exposures. Endothelial function (reactive hyperemia index [RHI]) was measured post-exposures (Thursdays). Black carbon (BC), total particle count (PC), PM2.5, noise and temperature were measured throughout exposures. RESULTS: PM2.5 (9.3 ± 7.7 µg/m3), BC (1.3 ± 0.6 µg/m3), PC (8,375 ± 4,930 particles/cm3) and noise (69.2 ± 4.2 dB) were higher (P values <0.01) and aortic hemodynamic parameters trended worse while near-roadway (P values<0.15 vs. exam room). Other outcomes were unchanged. Aortic hemodynamics trended towards improvements with N95 respirator usage while near-roadway (P values<0.15 vs. no-use), whereas other outcomes remained unaffected. Higher near-roadway PC and BC exposures were associated with increases in aortic augmentation pressures (P values<0.05) and trends toward lower RHI (P values <0.2). N95 respirator usage did not mitigate these adverse responses (nonsignificant pollutant-respirator interactions). Near-roadway outdoor-temperature and noise were also associated with cardiovascular changes. CONCLUSIONS: Exposure to real-world combustion-derived particulates in TRAP, even at relatively low concentrations, acutely worsened aortic hemodynamics. Our mixed findings regarding the health benefits of wearing N95 respirators support that further studies are needed to validate if they adequately protect against TRAP given their growing worldwide usage.