2007 Progress Report: Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects

EPA Grant Number: R832413C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R832413
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Southern California Particle Center
Center Director: Froines, John R.
Title: Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
Investigators: Nel, Andre E. , Harkema, Jack , Kleinman, Michael T. , Lusis, Aldons
Institution: University of California - Los Angeles , Michigan State University , University of California - Irvine
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2012)
Project Period Covered by this Report: October 1, 2006 through September 30, 2007
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

The primary objective is to elucidate the mechanism(s) of PM-induced asthma and atherosclerosis exacerbation. Mechanisms are investigated through in vivo animal studies in a mobile trailer suitable for exposure to ambient PM as well as in vitro studies of tissue culture cells.

Progress Summary:

  1. ApoE knockout mice exposed to CAPs on the freeway shows increased atherogenic potential of ultrafines (1)
  2. Epidemiological studies unveil that exposure to ambient particulate matter (PM) increases cardiovascular morbidity and mortality. Both epidemiological and animal-based works suggest that exacerbation of atherosclerosis is an important mechanism. Thus, intrapharyngeal instillation of PM10 and exposure to PM2.5 concentrated ambient particles (CAPs, aerodynamic diameter < 2.5 μm) has resulted in increased atherosclerosis in hypercholesterolemic Watanabe rabbits and apoE null mice respectively. We hypothesized that PM synergizes with known proatherogenic stimuli and mediators in their ability to elicit oxidative stress and promote atherosclerosis, and that most of the pro-inflammatory potential resides in the ultrafine particles (aerodynamic diameter <0.1 μm, UFP) that are highly enriched for redox cycling PM chemicals.

    We have conducted two experimental protocols (1). In the first (chow protocol), 6-week-old male C57BL/6J apoE null mice were placed on a chow diet and exposed to CAPs over a 40-day period, while in the second study (HFD protocol), 2-month-old male apoE null mice were fed a high fat diet (HFD) over a 56-day period. Food and water were administered ad libitum. Animals were euthanized 24-48 hours after completion of the last CAPs exposure, and aortas and various organs harvested. Animals in the non-exposed (NE) group were kept in the UCLA vivarium while mice destined for CAPs exposure were transported to the mobile research laboratory in downtown of Los Angeles, close (~300 m) to the I-110 freeway. Mice were housed in a Hazelton Chamber ventilated with air from which 99.9% of the incident particles were removed using a HEPA filter (chow protocol) or in top-filter cages (HFD protocol). Other than the NE group, there were three exposure groups (17-18 mice/group), namely filtered air (FA), particles < 2.5 μm (FP) and particles < 0.18 μm (UFP). Whole body exposures were performed simultaneously for five hours per day (exposure session), three days per week, for a combined total of 75 and 125 hours in the chow-fed and HFD-fed protocols, respectively.

    Chow-fed apoE null mice exposed to concentrated ultrafines developed significantly (p<0.05) larger early aortic atherosclerotic lesions (33011 +/- 3741, n=15) than animals exposed to PM2.5 (26361 +/- 2275, n= 16), filtered air (21362 +/- 2864, n= 14) or left non-exposed (17261 +/- 1659, n= 17) (1). Exposure to ultrafine particles resulted in an inhibition of the anti-inflammatory capacity of plasma high density lipoproteins and increased systemic oxidative stress markers as evidenced by a significant: (i) increase in hepatic malondialdehyde levels, (ii) upregulation of Nrf2-related phase-2 response genes (e.g., catalase, superoxide dismutase) when compared to filtered air or not exposed mice (1). While HFD-fed apoE null mice did not exhibit differences in their aortic atherosclerosis, they still show evidence of increased systemic oxidative stress as evidenced by significant upregulation of Nrf2 and Nrf2-regulated genes.

  3. Gene cluster analyis in human microvascular endothelial cells reveals a synergistic response to oxidized LDL components and pro-oxidative DEP chemicals (2)
  4. We have used human microvascular endothelial cells (HMEC) to test the hypothesis that pollutant particles synergize with known proatherogenic stimuli and mediators in their ability to elicit oxidative stress and promote atherosclerosis (2). We study the combined effects of a model air pollutant, diesel exhaust particles (DEP), and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (ox-PAPC) on genome-wide gene expression. We treated HMEC in triplicate wells with an organic DEP extract (5 μg/ml), ox-PAPC (10, 20 and 40 μg/ml) or combination of both compounds for 4 hours. Gene expression profiles were assessed by Illumina microarray technology. We found that both ox-PAPC and DEP regulated a large number of genes in a dose-dependent fashion that was evident for both upregulated and downregulated genes (2). More importantly, a marked degree of co-regulation was present where the combined action of DEP and ox-PAPC resulted in a different effect than DEP and ox-PAPC alone. All together, 1555 genes were significantly upregulated (> 1.5 fold, p < 0.05) by the three DEP and ox-PAPC combinatory treatments. Notably, some genes were uniquely regulated by ox-PAPC and not by DEP, and vice versa, some genes were regulated by DEP but not by ox-PAPC.

    We used weighted gene co-expression network analysis (WGCNA) to identify 12 modules of densely interconnected genes that were given unique color codes (2). We found three modules (Brown, Green and Yellow) that were most highly enriched in genes that were differentially regulated by the stimuli. Interestingly, all these three modules exhibited patterns of additive/synergistic interaction where the combined action of DEP and ox-PAPC resulted in a greater effect than each compound alone. We developed a novel synergistic index that allows us to differentiate in between additive effects and synergistic effects. Conceptually, we defined as the presence of a co-regulatory effect by both DEP and ox-PAPC that was greater than the effects induced by either compound alone and greater than the summation of those individual effects. Interestingly, the brown, green and yellow modules concentrated 83% of the synergistically expressed genes identified in the gene network. These three modules were also enriched in synergistically coregulated genes and pathways relevant to vascular inflammation. We validated our gene expression data by quantitative PCR (qPCR) in the same set of samples analyzed by microarray analysis and in a set of samples from an independent experiment. Representative genes from various pathways were selected including EpRE regulated genes [e.g. HO-1, selenoprotein S (SELS)], inflammatory response genes [e.g. Interleukin 8 (IL-8), chemokine (C-X-C motif) ligand 1 (CXCL1)], immune response genes [e.g. Interleukin 11 (IL-11)], UPR genes [e.g. ATF 4, heat shock 70kDa protein 8 (HSPA8), X-box binding protein 1 (XBP1)], oxygen and reactive oxygen species metabolism genes [e.g. dual specificity phosphatase 1 (DUSP1), PDZ and LIM domain 1 (PDLIM1)]. All of these genes were synergistically co-regulated by DEP and ox-PAPC in at least one combinatorial treatment. qPCR could confirm 91 % of the synergistic effects that were revealed by microarray technology (2).

    We validated this synergy on selected genes in vivo by demonstrating that liver gene expression of hypercholesterolemic mice (HFD protocol from section 1) exposed to ambient ultrafine particles exhibited significant upregulation of the module genes (2). Indeed, liver tissue was assayed for mRNA expression of HO-1, as well as two key UPR transcription factors, XBP1 and ATF4. UFP-exposed animals exhibited a significant up-regulation (p < 0.05) of all three genes in comparison with FP, FA and NE mice. These results indicate that the synergistic effects predicted by our in vitro studies have important in vivo outcomes, in which pro-oxidative PM chemicals may gain access to the systemic circulation from the lung and may then be able to synergize with circulating ox-LDL.

  5. Exposure to pro-oxidative DEP chemicals perturb the antigen-presenting function of dendritic cells, which may explain the adjuvant effect of PM in asthma (3)
  6. Dendritic cells (DCs) play a key role in antigen presentation in the immune system. There is growing evidence that the redox equilibrium of DCs influence their ability to induce T-cell activation and to regulate the polarity of immune response. Ambient particulate matter (PM) has been shown to act as an adjuvant that promotes sensitization to common environmental allergens. Systematic dissection of the molecular pathways of PM-induced adjuvancy is of great general interest and it is also a key priority in the research of asthma and allergy. We are studying the hypothesis that altered cellular redox equilibrium by PM and adsorbed redox cycling organic chemicals leads to the perturbation of DC function and favors Th2 skewing of the immune response. During the second year, we investigated how DEP chemical-induced oxidative stress interferes with DC function including maturation, antigen uptake, antigen presentation, expression of costimulatory molecule, cytokine/chemokine production, and T-cell activation (3). DCs were prepared from mouse bone marrow cells. Exposure of DCs to organic DEP extract (DEPext) resulted in a dose-dependent glutathione depletion and the induction of antioxidant enzyme, heme oxygenase-1 (HO-1) (3). Although DEP chemicals per se did not change the expression of DC surface molecules (I-Ad, CD54, and CD86), DEPext was able to suppress LPS-induced expression of these molecules in a dose-dependent fashion. Similarly, while DEPext alone failed to exert an effect on IL-12p40 and IL-12p70 production by DCs, it suppressed the LPS-induced production of this cytokine (3). The inhibitory effects of DEPext on LPS-induced CD86 expression and IL-12 production could be neutralized by thiol antioxidant, N-acetyl cysteine, indicating the involvement of oxidative stress. Using CD4+ T cells from a T-cell receptor transgenic mouse strain (DO11.10) that recognizes OVA323-339 in the context of the BALB/c MHC class II (I-Ad), we demonstrate that simultaneous exposure of DCs to DEPext and LPS induced a significant decrease in IFN-γ production compared with that in the cells treated with LPS only. Furthermore, exposure of DCs to DEPext alone, before antigen pulsing, significantly increased IL-10, a Th2 cytokine, production in the co-cultured T cells. In addition to inhibiting LPS effect (TLR4), organic DEP chemicals also suppressed CD86 expression induced by TLR2, TLR3, and TLR9 agonists suggesting that TLRs may be targets of DEP chemicals (3). Using BMDCs from Nrf2-deficient mice, we show that Nrf2 is required for the suppression of LPS effects by DEP chemicals. We demonstrate that DEPext inhibits LPS effects on DC by interfering with NFkB signaling pathway. The findings from the our second-year studies indicate that organic DEP chemicals indeed alter the redox equilibrium in DCs and that oxidative stress does interfere with several DC functions leading to the suppression of Th1 response (3). Our studies also indicate that Nrf2-mediated phase II response and NF-κB signaling pathway play keys roles in modulating DC function under conditions of PM-induced oxidative stress.

  7. Establishment of an in vivo mouse model for demonstrating the adjuvant effect of ultrafine particles on allergic sensitization
  8. Although studies have suggested that ambient PM can act as an adjuvant to promote sensitization to common environmental allergens, there is a paucity of direct evidence showing this effect on allergic sensitization in vivo. We have developed a mouse model, which allows us to demonstrate the adjuvant effect of ambient ultrafine particles (UFP) on ovalbumin (OVA)-induced allergic sensitization in vivo. In this model, Balb/C mice are intranasally sensitized with a low dose of endotoxin-free OVA (10 μg) in the absence or presence of ambient PM followed by OVA (1%) aerosol challenge. At a dose of 0.5 μg/mouse, UFP enhanced OVA-induced eosinophil infiltration, airway inflammation, and serum OVA-specific IgE and IgG1 production. IL-5 levels in the bronchoalveolar lavage fluid (BALF) were also increased in the animals that received UFP plus OVA. Using different controls, we were able to show that neither endotoxin nor ultrafine carbon black particles had any enhancing OVA sensitization. Moreover, side by side comparison of UFP and FP indicate that this adjuvant effect is specific to the UFP since FP failed to enhance the effect of OVA. This approach could therefore allow us to compare the contribution of particle size and accompanying differences in the pro-oxidative potential of PM2.5 and ultrafine particles in an in vivo model, similar to what we have previously demonstrated in tissue culture cells (Li et al, Environ. Health Perspect. 111:455-460; 2003). This model will also be employed in our CAPS exposure studies using particle concentrator technology (see below).

    We conducted one aerosolized ambient CAPs exposure experiment using this animal model. Animal exposure was carried out in the mobile exposure laboratory near downtown Los Angeles. To allow the mice time to adapt, they were brought from UCLA and placed in a Hazelton 1000 stainless steel, whole-body exposure chamber supplied with HEPA-filtered room air (10 air changes/hour) 2 days prior to the first exposure. The CAPs exposure took place in 0.32 cubic meter polycarbonate inhalation chambers, which were connected to the particle concentrators. CAPs were introduced under a slight vacuum (~2 inch water pressure) into the inhalation chambers using the VACES system. The targeted mass concentration for fine particles was approximately 600 ± 100 μg/m3 with at least 7-10 air changes/hour. The number concentration of UFP was expected to exceed 106 particles/cm3 after concentration enrichment. There were 3 inhalation exposure groups, namely (i) filtered air (FA), (ii) fine particles (FP), and (iii) ultrafine particles (UFP), in which each animal was sensitized by OVA (10 μg) via intranasal droplet. The positive control group received intranasal sensitization together with 0.5 μg UFP per mouse as described in section 4. The negative controls were non-sensitized and did not receive any PM. All animals in inhalation exposure and positive control groups received one dose of PM on day 1 followed by 4 times of OVA plus PM treatment on days 2, 5, 7, and 9. All animals were challenged on day 22 and 23 with 1% OVA aerosol and sacrificed on day 24.

    BALF and lung morphometry were analyzed to determine the impact of ambient fine particles and UFP on OVA sensitization. BALF cytology showed that mice in the positive control group had more total cells compared to any of the other experimental groups. There was a significant increase of neutrophils, lymphocytes, and eosinophils in the positive control (intranasal) group compared to negative-control mice. The number of total cells, neutrophils, lymphocytes, and esosinophils were also significantly greater in positive control group compared to FA, FP, or UFP. However, the number of cells in the BALF recovered from the aerosolized FP or UFP did not differ from the animals exposed FA.

    No histopathology was microscopically detectable in negative-control mice. In contrast, the positive-control mice (intranasal UFP) had conspicuous lung lesions that were consistent with OVA-induced allergic airway disease. There was moderate to marked mucous cell metaplasia in the airway epithelium lining large diameter, pre-terminal bronchioles primarily along the main axial pathways. This airway metaplastic change was evident in both the proximal and distal lung sections. Mucous cell metaplasia did not extend to terminal bronchioles. Along with this airway epithelial change, the lungs of positive control mice also had a peribronchiolar and perivascular, mixed inflammatory cell infiltrate composed mainly of large and small lymphocytes and plasma cells, lesser numbers of eosinophils, and occasional neutrophils.

    Mice in the ambient aerosolized FA, FP, and UFP groups had similar OVA-induced lung lesions as those of the positive-control mice, but the severity of these lesions were drastically less. The severity of the pulmonary lesions among the OVA-treated groups of mice exposed by inhalation did not differ, suggesting that neither aerosolized fine nor ultrafine CAPs altered the lung’s response to OVA. This was in contrast to the profound increase in the severity of OVA-induced lung lesions caused by intranasal UFP instillation in the positive-control mice.

    Quantitative estimate of the severity of mucous cell metaplasia was assessed by morphometry of intraepithelial mucosubstances in bronchiolar airways. Little or no AB/PAS-stained mucosubstances were evident in the airway epithelium lining the proximal or distal main axial airways of negative control mice. Positive-control mice had more intraepithelial mucosubstances (IM), in either the proximal or distal axial airway, than mice in any of the other groups. All of the mice in the OVA-treated groups had markedly more IM than that in the negative-control mice, but there was significantly more IM in the positive control mice compared to those in FA, FP, and UFP groups, especially in the distal axial airway. There were no significant differences in the amount of IM among the FA, FP, and UFP groups, indicating again that CAPs inhalation exposure did not alter the magnitiude of the OVA-induced mucous cell metaplasia.

    Taken together, these results suggest that intranasal OVA delivery caused minimal allergic airway, epithelial and inflammatory responses in the lungs of mice without concomitant intranasal UFP instillation. Thus, intranasal UFP exert an adjuvant effect that could not be obtained with intranasal fine PM. In contrast, exposures to aerolized fine or ultrafine CAPs did not alter the OVA-induced pulmonary lesions or changes in BALF in the mice exposed by inhalation. A possible explanantion of this discrepancy is that the aerosolized particles are not effectively delivered to the same mucosal site as the allergen (OVA), thereby depriving the antigen-presenting DC from the PM-delivered oxidative stress stimulus that is required to prime these cells for promoting in vivo allergen sensitization (see #3 above).

  9. Proteome analysis of the oxidative stress response in a bronchial epithelial cell line exposed to an organic DEP extract
  10. Ambient particulate matter (PM) induces adverse health effects through the ability of pro-oxidative chemical compounds to induce the production of oxygen radicals and oxidant injury. We have previously demonstrated that organic redox cycling diesel exhaust particle (DEP) chemicals induce a tiered oxidative stress response in a macrophage cell line as determined by proteome analysis (Xiao at al; J Biol Chem, 278:50781-50790; 2003). Utilizing a proteome-based strategy involving 2D-difference gel electrophoresis (DIGE) and immunoblotting, assisted by real-time PCR, we have now obtained eveidence that a methanol DEP extract induce an unfolding protein response (UPR) and pro-inflammatory effects in the human bronchial epithelial cell line, BEAS-2B. DIGE analysis and mass spectrometry showed the induction of at least 14 proteins, among which HSP70, HSP40, TPR repeat protein 2, and T-complex protein 1 (zeta-subunit) are known to play a role in the UPR. We are currently performing immunoblotting and RT-PCR analyis to determine which of these proteins respond to the DEP extract as well as whether the response is sensitive to the effect of the thiol antioxidant, N-acetylcysteine. Taken together, our data suggest that pro-oxidative DEP chemicals induce protein unfolding and misfolding that leads to an UPR and pro-inflammatory effects in a cell type that is targeted by PM in the lung. These data are being written up.

    Neurological consequences of PM exposure

    We have examined the association between exposure to PM and adverse CNS effects in apolipoprotein E knockout (ApoE-/-) mice exposed to two levels of concentrated ultrafine PM in central Los Angeles. The exposure details were presented elsewhere under Project 2 in this report. Although these mice were exposed primarily to examine the role of PM in the development of cardiovascular disease, the ApoE-/- mouse is also recognized as a good model for neurodegenerative disease studies. Mice were euthanized 24 hr after the last exposure and tissue was harvested and frozen for subsequent bioassays. There was clear evidence of aberrant immune activation in the brains of exposed animals as judged by a dose-related increase in nuclear translocation of two key transcription factors, NF-κB and AP-1. These factors are involved in the promotion of inflammation. Increased levels of glial fibrillary acidic protein (GFAP) were also found consequent to the low level particulate inhalation exposure suggesting that glial activation was taking place but that response was attenuated after exposures at high levels. In order the determine the mechanism by which these events occurred, levels of several MAP kinases involved in activation of these transcription factors were assayed by Western blotting. There were no significant changes in the proportion of active (phosphorylated) forms of ERK-1, IkB and p38. However fraction of JNK in the active form was significantly increased in animals receiving the lower concentration of concentrated ambient particle (CAPs), but not the higher concentration. These data suggest that glial cells may be involved in the brain’s inflammatory response to inhaled ultrafine particles, that the signaling pathway by which these transcription factors are activated may involve the activation of JNK and that the dose response profile may not be monotonic.

Future Activities:

In the next year, we will continue our studies to address the role of CAPs in animal asthma and atherosclerosis models with a focus on dissecting the mechanisms by which PM-induced oxidative stress interferes with the function of endothelial and dendritic cells. We will continue to address the role of CAPs in murine atherosclerosis. We will focus on the effect of UFP exposure on plasma HDL. We will also explore the effect of UFP-induced oxidative stress on the susceptibility of animals to atherosclerosis using Nrf2 deficient mice. The role of Nrf2 in regulating DC response to PM chemicals will be explored by exposing DCs from wild-type and Nrf2 deficient mice to DEPext­ and OVA ex vivo followed by adoptive transfer to determine whether Nrf2 deficiency renders animals more susceptible to DEP redox active chemicals. We will also use our intranasal sensitization model to sensitize the animals with OVA plus DEP fractions of different redox activities (aliphatic, aromatic, and polar) to identify the pro-oxidative chemical groups that are responsible for the adjuvant effect of UFP.


Journal Articles on this Report : 7 Displayed | Download in RIS Format

Other subproject views: All 34 publications 23 publications in selected types All 23 journal articles
Other center views: All 241 publications 157 publications in selected types All 157 journal articles
Type Citation Sub Project Document Sources
Journal Article Araujo JA, Barajas B, Kleinman M, Wang X, Bennett BJ, Gong KW, Navab M, Harkema J, Sioutas C, Lusis AJ, Nel AE. Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circulation Research 2008;102(5):589-596. R832413 (2008)
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  • Journal Article Chan RC-F, Wang M, Li N, Yanagawa Y, Onoe K, Lee JJ, Nel AE. Pro-oxidative diesel exhaust particle chemicals inhibit LPS-induced dendritic cell responses involved in T-helper differentiation. Journal of Allergy and Clinical Immunology 2006;118(2):455-465. R832413 (2008)
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  • Journal Article Chatila TA, Li N, Garcia-Lloret M, Kim H-J, Nel AE. T-cell effector pathways in allergic diseases:transcriptional mechanisms and therapeutic targets. Journal of Allergy and Clinical Immunology 2008;121(4):812-823. R832413 (2007)
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  • Journal Article Gong KW, Zhao W, Li N, Barajas B, Kleinman M, Sioutas C, Horvath S, Lusis AJ, Nel A, Araujo JA. Air-pollutant chemicals and oxidized lipids exhibit genome-wide synergistic effects on endothelial cells. Genome Biology 2007;8(7):R149 (13 pp.). R832413 (2008)
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  • Journal Article Li N, Xia T, Nel AE. The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles. Free Radical Biology and Medicine 2008;44(9):1689-1699. R832413 (2007)
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  • Journal Article Xia T, Kovochich M, Nel A. The role of reactive oxygen species and oxidative stress in mediating particulate matter injury. Clinics in Occupational and Environmental Medicine 2006;5(4):817-836. R832413 (2008)
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  • Journal Article Xia T, Kovochich M, Nel AE. Impairment of mitochondrial function by particulate matter (PM) and their toxic components: implications for PM-induced cardiovascular and lung disease. Frontiers in Bioscience 2007;12(4):1238-1246. R832413 (2008)
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  • Supplemental Keywords:

    Asthma, atherosclerosis, oxidative stress, ambient PM, health effects, sensitive populations, human health, animal, PAH, gene co-expression network analysis, synergy, dendritic cell, adjuvant,, RFA, Health, Scientific Discipline, Air, particulate matter, Toxicology, Health Risk Assessment, Risk Assessments, Biochemistry, Ecology and Ecosystems, atmospheric particulate matter, particulates, human health effects, PM 2.5, animal model, airway disease, airborne particulate matter, cardiovascular vulnerability, air pollution, human exposure, vascular dysfunction, cardiovascular disease, human health risk

    Progress and Final Reports:

    Original Abstract
  • 2006 Progress Report
  • 2008 Progress Report
  • 2009 Progress Report
  • 2010 Progress Report
  • 2011
  • Final Report

  • Main Center Abstract and Reports:

    R832413    Southern California Particle Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832413C001 Contribution of Primary and Secondary PM Sources to Exposure & Evaluation of Their Relative Toxicity
    R832413C002 Project 2: The Role of Oxidative Stress in PM-induced Adverse Health Effects
    R832413C003 The Chemical Properties of PM and their Toxicological Implications
    R832413C004 Oxidative Stress Responses to PM Exposure in Elderly Individuals With Coronary Heart Disease
    R832413C005 Ultrafine Particles on and Near Freeways