Payam Pakbin

Prenatal Exposure to Urban Air Nanoparticles in Mice Causes Altered Neuronal Differentiation and Depression- Like Responses

Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re-aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re-aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 µg/m3) or control filtered ambient air for 10 weeks (3×5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 µg/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols.

Spatial and Temporal Variability of Coarse (PM10−2.5) Particulate Matter Concentrations in the Los Angeles Area

Recent epidemiological and toxicological studies suggest that coarse particulate matter (CPM, particles smaller than 10 and larger than 2.5 μm in diameter, PM 10−2.5 ) concentrations may be associated with adverse health outcomes at levels similar to or larger than those associated with PM 2.5 concentrations. CPM may consist of several, mechanically generated, potentially toxic components, including re-suspended road dust, industrial materials, trace metals, and bio-aerosols. In an effort to better understand and quantify the linkage between sources, composition and the toxicity of coarse PM, 10 sampling sites were set-up in the Los Angeles area. Sites within this diverse monitoring network were selected to encompass urban, rural, coastal, inland, near-freeway, community-based, upwind pollutant “source” and downwind pollutant “receptor” sites to fully characterize the range of likely conditions. At each location, a 24 h time-integrated coarse PM sample was collected once per week for one year in order to assess the seasonal and spatial patterns in coarse PM concentrations. Annual geometric mean CPM mass concentrations varied from <5.0 μg/m 3 to approximately 12 μg/m 3 . Concentrations were 2–4 times higher in the summer than the winter. CPM correlations between sites in close proximity to each other tended to be high (r 2 > 0.80), but were poor between urban center and inland sites. The coefficients of divergence (COD) were also calculated across all site pairs to quantify CPM mass concentration spatial heterogeneity. The CODs (most monthly median values >0.2) suggest modest heterogeneity overall, but the CODs calculated between the urban core site pairs were homogeneous.

Intra-Community Variability in Total Particle Number Concentrations in the San Pedro Harbor Area (Los Angeles, California)

Recent evidence links elevated ultrafine particle (UFP) concentrations with adverse health effects, but exposure assessments based upon PM 2.5 mass concentrations may be misleading. In order to better understand and quantify intra-community variability in UFP concentrations, a dense network of 14 monitoring sites was set-up in Los Angeles in two clusters—San Pedro/Wilmington and West Long Beach—in communities surrounding the Ports of Los Angeles and Long Beach. The network measured total particle number concentrations greater than 7 nm in diameter. In this range, UFP comprise approximately 90% of the total. Port-related activities—particularly goods movement associated with high volumes of heavy-duty diesel vehicle (HDDV) traffic—represent significant UFP sources. The field study was conducted from mid-February through mid-December 2007 to assess diurnal, seasonal, and spatial patterns and intra-community variability in total particle number concentrations. For sites within a few km of each other, simultaneous particle number concentrations can vary up to a factor of 10 (< 10,000 cm−3 up to 90,000 cm−3 for hourly averages calculated by month). The median hourly correlation coefficient (r) across all sites was modest and varied from 0.3 to 0.56. Specific site locations, particularly proximity to roadways used for goods movement, strongly affect observations. Clear diurnal and seasonal patterns are evident in the data. A diurnal pattern associated with high HDDV volumes and goods movement was identified. Coefficients of Divergence calculated for the site pairs suggest moderate heterogeneity overall (median study COD ≈ 0.35). The intra-urban variability observed in this study is comparable to and exceeds the inter-urban variability observed in a previous study in Los Angeles. UFP concentrations can vary considerably on short spatial scales in source-rich environments strongly influencing the accuracy of exposure assessments.

Seasonal and Spatial Coarse Particle Elemental Concentrations in the Los Angeles Area

The concentrations of trace metals and elements in the coarse fraction of atmospheric particulate matter (CPM, particles smaller than 10 and larger than 2.5 μm in diameter, PM10–2.5) and their spatial and temporal trends were investigated in the greater Los Angeles area. Ten distinct sampling sites were chosen to encompass a variety of CPM sources, including urban, rural, coastal, inland, and near-freeway sites. Time-integrated 24-h CPM samples were collected at each location once a week, for an entire year, from April 2008 to March 2009, to characterize drivers of the seasonal and spatial patterns of the CPM trace metal content. Metals were quantified using sector-field inductively coupled plasma mass spectrometry (SF-ICP-MS). Trace metals in CPM displayed distinct seasonal and temporal variations, and a principal component analysis (PCA) was performed to aid the identification of the CPM sources underlying these variations. The probable sources of each principal component were identified using elemental tracers. Major sources of CPM metals and elements identified were crustal and mineral matter, abrasive vehicular emissions, industrial, sea spray, and catalytic converters, explaining more than 80% of the total variance of CPM metal content. Mineral and crustal elements, most notably Fe, Ca, Al, Mg, K, Ti, and Mn, were the main contributors to the overall CPM mass, accounting for over 33% of the total variance, followed by abrasive vehicular markers such as Cu, Ba, and Sb, accounting for over 16% of the variance, with an increasing contribution in the urban sites. Temporal and spatial variations in each identified class of CPM sources were also investigated.

Ambient Ultrafine Particles Alter Lipid Metabolism and HDL Anti-Oxidant Capacity in LDLR-null Mice

Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular diseases. The redox-active ultrafine particles (UFPs) promote vascular oxidative stress and inflammatory responses. We hypothesized that UFPs modulated lipid metabolism and anti-oxidant capacity of high density lipoprotein (HDL) with an implication in atherosclerotic lesion size. Fat-fed low density lipoprotein receptor-null (LDLR−/−) mice were exposed to filtered air (FA) or UFPs for 10 weeks with or without administering an apolipoprotein A-I mimetic peptide made of D-amino acids, D-4F. LDLR−/− mice exposed to UFPs developed a reduced plasma HDL level (P < 0.01), paraoxonase activity (P < 0.01), and HDL anti-oxidant capacity (P < 0.05); but increased LDL oxidation, free oxidized fatty acids, triglycerides, serum amyloid A (P < 0.05), and tumor necrosis factor α (P < 0.05), accompanied by a 62% increase in the atherosclerotic lesion ratio of the en face aortic staining and a 220% increase in the cross-sectional lesion area of the aortic sinus (P < 0.001). D-4F administration significantly attenuated these changes. UFP exposure promoted pro-atherogenic lipid metabolism and reduced HDL anti-oxidant capacity in fat-fed LDLR−/− mice, associated with a greater atherosclerotic lesion size compared with FA-exposed animals. D-4F attenuated UFP-mediated pro-atherogenic effects, suggesting the role of lipid oxidation underlying UFP-mediated atherosclerosis.

Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine.

Background: Exposure to ambient ultrafine particulate matter (UFP) is a well-recognized risk factor for cardiovascular and respiratory diseases. However, little is known about the effects of air pollution on gastrointestinal disorders. Objective: We sought to assess whether exposure to ambient UFP (diameter < 180 nm) increased free fatty acids and lipid metabolites in the mouse small intestine. Methods: Ldlr-null mice were exposed to filtered air (FA) or UFP collected at an urban Los Angeles, California, site that was heavily affected by vehicular emissions; the exposure was carried out for 10 weeks in the presence or absence of D-4F, an apolipoprotein A-I mimetic peptide with antioxidant and anti-inflammation properties on a high-fat or normal chow diet. Results: Compared with FA, exposure to UFP significantly increased intestinal hydroxyeicosatetraenoic acids (HETEs), including 15-HETE, 12-HETE, 5-HETE, as well as hydroxyoctadecadienoic acids (HODEs), including 13-HODE and 9-HODE. Arachidonic acid (AA) and prostaglandin D2 (PGD2) as well as some of the lysophosphatidic acids (LPA) in the small intestine were also increased in response to UFP exposure. Administration of D-4F significantly reduced UFP-mediated increase in HETEs, HODEs, AA, PGD2, and LPA. Although exposure to UFP further led to shortened villus length accompanied by prominent macrophage and neutrophil infiltration into the intestinal villi, administration of D-4F mitigated macrophage infiltration. Conclusions: Exposure to UFP promotes lipid metabolism, villus shortening, and inflammatory responses in mouse small intestine, whereas administration of D-4F attenuated these effects. Our findings provide a basis to further assess the mechanisms underlying UFP-mediated lipid metabolism in the digestive system with clinical relevance to gut homeostasis and diseases. Citation: Li R, Navab K, Hough G, Daher N, Zhang M, Mittelstein D, Lee K, Pakbin P, Saffari A, Bhetraratana M, Sulaiman D, Beebe T, Wu L, Jen N, Wine E, Tseng CH, Araujo JA, Fogelman A, Sioutas C, Navab M, Hsiai TK. 2015. Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine. Environ Health Perspect 123:34–41; http://dx.doi.org/10.1289/ehp.1307036

Atmospheric ultrafine particles promote vascular calcification via the NF-κB signaling pathway

Exposure to atmospheric fine particulate matter (PM(2.5)) is a modifiable risk factor of cardiovascular disease. Ultrafine particles (UFP, diameter <0.1 μm), a subfraction of PM(2.5), promote vascular oxidative stress and inflammatory responses. Epidemiologic studies suggest that PM exposure promotes vascular calcification. Here, we assessed whether UFP exposure promotes vascular calcification via NF-κB signaling. UFP exposure at 50 μg/ml increased alkaline phosphatase (ALP) activity by 4.4 ± 0.2-fold on day 3 (n = 3, P < 0.001) and matrix calcification by 3.5 ± 1.7-fold on day 10 (n = 4, P < 0.05) in calcifying vascular cells (CVC), a subpopulation of vascular smooth muscle cells with osteoblastic potential. Treatment of CVC with conditioned media derived from UFP-treated macrophages (UFP-CM) also led to an increase in ALP activities and matrix calcification. Furthermore, both UFP and UFP-CM significantly increased NF-κB activity, and cotreatment with an NF-κB inhibitor, JSH23, attenuated both UFP- and UFP-CM-induced ALP activity and calcification. When low-density lipoprotein receptor-null mice were exposed to UFP at 359.5 μg/m(3) for 10 wk, NF-κB activation and vascular calcification were detected in the regions of aortic roots compared with control filtered air-exposed mice. These findings suggest that UFP promotes vascular calcification via activating NF-κB signaling.

Diurnal and seasonal trends in the apparent density of ambient fine and coarse particles in Los Angeles

Diurnal and seasonal variations in the apparent density of ambient fine and coarse particulate matter (PM2.5 and CPM [PM2.5-10], respectively) were investigated in a location near downtown Los Angeles. The apparent densities, determined by particle mass-to-volume ratios, showed strong diurnal and seasonal variations, with higher values during the warm phase (June to August 2013) compared to cold phase (November 2012 to February 2013). PM2.5 apparent density showed minima during the morning and afternoon rush hours of the cold phase (1.20g cm(-3)), mainly due to the increased contribution of traffic-emitted soot particles, and highest values were found during the midday in the warm phase (2.38g cm(-3)). The lowest CPM apparent density was observed during the morning rush hours of the cold phase (1.41g cm(-3)), while highest in early afternoon during the warm phase (2.91g cm(-3)), most likely due to the increased wind-induced resuspension of road dust.

Associations of oxidative stress and inflammatory biomarkers with chemically-characterized air pollutant exposures in an elderly cohort

BACKGROUND Exposure to air pollution has been associated with cardiorespiratory morbidity and mortality. However, the chemical constituents and pollution sources underlying these associations remain unclear. METHOD We conducted a cohort panel study involving 97 elderly subjects living in the Los Angeles metropolitan area. Airway and circulating biomarkers of oxidative stress and inflammation were measured weekly over 12 weeks and included, exhaled breath condensate malondialdehyde (EBC MDA), fractional exhaled nitric oxide (FeNO), plasma oxidized low-density lipoprotein (oxLDL), and plasma interleukin-6 (IL-6). Exposures included 7-day personal nitrogen oxides (NOx), daily criteria-pollutant data, five-day average particulate matter (PM) measured in three size-fractions and characterized by chemical components including transition metals, and in vitro PM oxidative potential (dithiothreitol and macrophage reactive oxygen species). Associations between biomarkers and pollutants were assessed using linear mixed effects regression models. RESULTS We found significant positive associations of airway oxidative stress and inflammation with traffic-related air pollutants, ultrafine particles and transition metals. Positive but nonsignificant associations were observed with PM oxidative potential. The strongest associations were observed among PM variables in the ultrafine range (PM <0.18µm). It was estimated that an interquartile increase in 5-day average ultrafine polycyclic aromatic hydrocarbons was associated with a 6.3% (95% CI: 1.1%, 11.6%) increase in EBC MDA and 6.7% (95% CI: 3.4%, 10.2%) increase in FeNO. In addition, positive but nonsignificant associations were observed between oxLDL and traffic-related pollutants, ultrafine particles and transition metals while plasma IL-6 was positively associated with 1-day average traffic-related pollutants. CONCLUSION Our results suggest that exposure to pollutants with high oxidative potential (traffic-related pollutants, ultrafine particles, and transition metals) may lead to increased airway oxidative stress and inflammation in elderly adults. This observation was less clear with circulating biomarkers.

Is atherosclerotic disease associated with organic components of ambient fine particles

Heart disease is a major killer in western societies; coronary artery disease and atherosclerosis are important contributors to this mortality. Atherosclerosis in mice with a deleted apoE gene (apoE-/-) is accelerated by exposure to ambient ultrafine particles (UFP) which are particles smaller than 180 nm in diameter. UFP contain organic components that are pro-oxidant and may cause or aggravate heart disease. Could removal of these organic constituents mitigate adverse cardiovascular effects? ApoE-/- mice were exposed to concentrated UFP (CAP), CAP from which organic constituents were removed by thermal denuding (deCAP) or purified air (controls) for 5 hr/day, 4 days/week for 8 weeks. Heart rate (HR), heart rate variability (HRV), biomarkers of oxidative stress and the sizes of arterial plaques were measured. Adverse effects were seen in CAP-exposed mice (increased size of arterial plaque, increased oxidative stress and decreased HRV, compared to controls). Adverse effects were not observed in deCAP-exposed mice. Removal of organic constituents from ambient particles resulted in significant reduction of toxic cardiovascular effects of air pollution exposure.