2011 Progress Report: Animal models: Cardiovascular Disease, CNS Injury and Ultrafine Particle Biokinetics

EPA Grant Number: R832415C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R832415
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Rochester PM Center
Center Director: Oberdörster, Günter
Title: Animal models: Cardiovascular Disease, CNS Injury and Ultrafine Particle Biokinetics
Investigators: Oberdörster, Günter , Elder, Alison C.P. , Johnston, Carl G. , Oakes, David , Cory-Slechta, Deborah , Couderc, Jean-Philippe , Phipps, Richard , Gelein, Robert , Eberly, Shirley , Kreyling, Wolfgang
Current Investigators: Oberdörster, Günter , Elder, Alison C.P. , Oakes, David , Couderc, Jean-Philippe , Phipps, Richard , Gelein, Robert , Kreyling, Wolfgang
Institution: University of Rochester , GSF-National Research Center for Environment and Health
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: July 1, 2010 through June 30,2011
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

Project A:
Objective 1Determine CNS effects of exposure to concentrated ambient ultrafine particles in a sensitive triple- transgenic Alzheimer Disease mouse model (3xTgAD).
 
Objective 2aDetermine effects of early life exposure to ambient ultrafine particles of rats on the CNS. Investigators:  J. Allen, et al.
Objective 2b:  Are ambient ultrafine particles a risk factor for Parkinson’s Disease? Investigators:  J. Allen, et al.
 
Project B: Susceptibility of Developing Lung to UFPs via Inflammatory and ROS Mechanisms.
Objective 3Determine effects of early life exposure to ambient ultrafine particles and Ozone mixtures on the early and late pulmonary responses of mice re-challenged with ovalbumina.
 
Project C
Objective: Assess the usefulness of different modes of dosing the respiratory tract with PM, specifically ultrafine PM, to assess their inflammation potential.

Progress Summary:

Project A

Objective 1

Earlier studies in which 3xTg-AD mice were exposed for 12 days to ultrafine Mn oxide particles to examine progression of AD pathology showed increased microglia and astrocyte activation in the hippocampus as compared to filtered air-exposed controls.  Interestingly, evidence of heightened inflammatory cell activation was still found 2 months post-exposure. In a follow-up pilot study, we exposed transgenic mice to concentrated ambient ultrafine particles using our HUCAP (Harvard Ultrafine Concentrated Ambient Particle) system. The exposure was for 4 hrs on each of 8 days over a 2-week period. Average ultrafine particle number and mass concentrations were 1.5 x 105/cm-3 and 75.7 µg/m3 with an average particle size of 85.1 nm (count median diameter) and geometric standard deviation of 1.49.  In this pilot study, we also explored the role of tumor necrosis factor (TNF) receptor signaling in the activation of hippocampal microglia by using a compound transgenic mouse that exhibits both the 3xTg-AD phenotype and has knocked out TNF I and II receptors (TNFRI/II  KO).  Thus,  four  genotypes  were  included  in  the  study:  non-transgenic (non-Tg),  3xTg-AD, TNFRI/II KO, and 3xTg-ADxTNFRI/II KO.  Because this was a pilot study and resources were not available to expose mice to more than one atmosphere, there is no filtered air control group. Analyses of hippocampal sections at 2 months post-exposure showed that overall immunostaining for a microglial marker (Iba-1) was lower in TNFRI/II KO and 3xTg-ADxTNFRI/II KO mice as compared to non-Tg and 3xTg-AD mice.  When the immunostaining was evaluated on a cell-by-cell basis, it was found that there were fewer activated and more resting microglia in mice that lacked TNF receptors.  Because air-exposed controls were not available for comparisons, it is not possible to make conclusions about the impact of HUCAP exposure; this is the goal of future studies.

Objective 2a:

Increasing evidence suggests that ultrafine particulate matter (UFP) may adversely influence the brain, particularly early in development, a period of brain vulnerability. If so, air pollutants may represent a largely underappreciated contribution to CNS diseases and disorders. That hypothesis was tested in male and female C57BL6 mice exposed to concentrated ultrafine ambient particles (HUCAPs) at postnatal days (PN) 4-13, with a subset also re-exposed  as adults (Ad) at  56-60 days of age (PN + Ad).  Blood corticosterone levels were decreased in PN males 24 hrs after the final HUCAPs exposure, but increased in both PN and PN+Ad females, consistent with hypothalamic-pituitary-adrenal (HPA) axis dysfunction. In males, PN alone persistently suppressed overall response rates during acquisition of prototypical fixed interval (FI) operant schedule-controlled behavior; locomotor activity levels measured 2 wks after final HUCAPs exposure were comparably reduced in PN and PN+Ad groups.  In Ad females, FI overall response rates were increased, whereas locomotor activity levels were reduced in PN+AD, but not in PN alone groups, consistent with enhanced effects. Preliminary assessment of learning using novel object recognition suggests impairment in PN females.  Glial fibrillary acidic protein immunoreactivity, a marker of astrogliosis measured in mice sacrificed at 62 days of age, was still increased in midbrain, corpus callosum and hippocampus/dentate gyrus of mice (n=2-3/treatment) after PN only HUCAPs. Collectively, these findings indicate that ambient ultrafine particles can produce, differentially by gender, persistent behavioral, CNS and HPA dysfunction even following PN only exposure. Given that such exposures are persistent and possibly life-long, these results also support the hypothesis of the potential for particulate air pollution to be a risk factor for neurodevelopmental and/or neurodegenerative disorders.

Objective 2b:

Increasing data suggest that concentrated ambient particulate matter (CAPS) adversely impacts brain and could represent a largely underappreciated contribution to CNS diseases. Early development may be a period of particular vulnerability of brain to such damage. One mode of CAPS consists of ultrafine particles that may translocate from deposition sites on the nasal olfactory mucosa to the CNS. This study examines the hypothesis that early life postnatal to concentrated ambient ultrfine particles (HUCAPs) exposure would sensitize the CNS to subsequent adult challenge with paraquat + maneb (PQ+MB), a well-established pesticide-based model of the Parkinson’s disease phenotype (PDP).  Following HUCAPs exposure from PND 4-8 and 10-13 days, mice were subjected as adults to PQ (10 mg/kg) and MB (30 mg/kg) i.p. 2x week for 6 weeks. Mice exposed postnatally to HUCAPs were significantly more sensitive to the locomotor-reducing effects of PQ+MB than sham controls, or those exposed to HUCAPs alone or PQ+MB alone. HUCAPs and PQ+MB significantly altered catecholamine levels in both the nigrostriatal and mesocortical dopamine pathways. HUCAPs had a particular influence on striatum, increasing NE, DOPAC, and DA turnover (DOPAC/DA) levels, while PQ+MB generally impacted midbrain, decreasing 5HT, DOPAC and dopamine turnover. An interaction between HUCAPs and PQ+MB on cortical 5-HT levels was evidenced as a significant 5-HT decrease in PQ+MB treated animals compared to both sham controls and HUCAPs +PQ+MB treated mice. Cortical DA also was increased in PQ+MB treated animals.  Collectively, these findings indicate that early life HUCAPs enhances locomotor reduction in response to PQ+MB challenge and changes striatal catecholamines (DAergic cell terminals), a region critical to PD, while PQ+MB, in the same animals produces catecholamine changes in the ventral midbrain (DAergic cell bodies). Conceivably, this concurrent damage to striatum and midbrain could increase nigral cell death and thereby contribute to a PDP; future analyses will include assessment of TH immunoreactivity and stereological analysis of DAergic cell counts in the SNpc and VTA.

Significance to the field:

The potential of inhaled ultrafine particles of ambient particulate air pollution for inducing effects on the CNS has been suggested based on several toxicological and some recent epidemiological studies.  Knowledge of underlying direct and indirect mechanisms involving CNS translocation, role of adsorbed organic and inorganic chemicals and of systemically vs. locally induced effects is necessary for assessing the contribution of ultrafine particles to the induction of adverse effects by particulate air pollution.

Relationship to overall Center goals:

These studies are an obvious extension of our Center research focusing on ultrafine particles and their role in causing extrapulmonary effects, specifically with the CNS as a sensitive target organ.

Relevance to the Agency’s mission:

The ubiquitous ultrafine particle mode of ambient air pollution is not directly regulated with a specific National Ambient Air Quality Standard (NAAQS).  Given the diversity of ultrafine particle sources involving both anthropogenic and natural sources, a generic standard based on mass or number concentration would not be appropriate.  Rather, specific sources may be targeted in terms of reducing emissions, based on the identification of hazard of ultrafine particles emitted into the atmosphere.

Project B

Objective 3

Summary of PM Center Pilot Project:

Children may be affected by environmental contaminants in ways that adults are not, both because their exposures may be higher and because they may be more vulnerable to the toxic effects of the contaminants. Early life exposures may contribute to diseases, either during childhood or later in life. We hypothesized that early life exposure to ambient ultrafine particles alters lung response and structural development leading to increased sensitivity to low level environmental challenges as adults.  We have developed three studies to begin to address this hypothesis.

Progress Report: Balb C and NRF 2-/- mice were exposed to concentrated ambient particles (CAPS) and 0.3 PPM ozone mixture or vehicle (filtered air) from postnatal days 4-7 and 10-13 for 4 hrs/day between 0800 and 1200 hrs. Mice received re-exposure starting at either postnatal day 28 or 56.  At this time point, mice were vehicle exposed or sensitized to either ova or ova + LPS for 3 days.  Mice then were allowed to recover for 10 days after which they were challenged with vehicle, ova or ova + LPS for an additional 3 days.  Mice were allowed to recover for 48 hours and then were examined. Mice were re-exposed during the first 3 weeks of September and analysis is ongoing. Endpoints to be examined will be lavage analysis, airway hyper-reactivity, and cytokine measurements from whole lung homogenates.

Objective: Determine effects of early life exposure to ambient ultrafine particles mixed with ozone on later life environmental challenges.

Progress Report: C57Bl6 mice were exposed to concentrated ambient particles (CAPS) mixed with 0.3 PPM ozone, CAPs, ozone or vehicle (filtered air) from postnatal days 4-7 and 10-13 for 4 hrs/day between 0800 and 1200 hrs. Mice received adult re-exposure starting at 8 or 26 weeks post birth for an additional 4 days creating four exposure groups as follows: postnatal air/adult air, postnatal CAPS/adult CAPS, postnatal 0.3 PPM ozone /adult 0.3 PPM ozone, postnatal CAPS + ozone/adult CAPS + ozone.  A second group of mice will be exposed to influenza virus at the 26 week time point creating four exposure groups as follows:  postnatal CAPS + ozone/adult influenza, postnatal CAPS/adult influenza, postnatal 0.3 PPM/adult influenza, postnatal air/adult influenza.

Initial exposures occurred throughout the month of July.  Eight-week post-birth exposures have occurred throughout the month of September and analysis is ongoing.  Twenty-six-week exposures and analysis will begin in December of this year.  Endpoints to be examined will be cytokine and antioxidant mRNA analysis and lavage analysis. Histologic staining for surfactant and cytokines also will be done.

Objective: Determine effects of early life exposure to oxygen on later life re-exposure to ambient ultrafine particles mixed with low-level ozone.

Progress Report: C57Bl6 mice were exposed to 100% oxygen or vehicle (filtered air) from postnatal days 0-4. Mice received adult re-exposure starting at 8 or 26 weeks post birth for an additional 4 days creating four exposure groups as follows: postnatal air/adult CAPS/ozone, postnatal air/adult air, postnatal oxygen/adult air, postnatal oxygen/adult CAPS/ozone. Initial oxygen exposures occurred at the end of June, with the 8-week re-exposure occurring during the end of August. Twenty-six-week post-birth exposures will be done during November of this year. Endpoints to be examined will be cytokine and antioxidant mRNA analysis and lavage analysis. Histologic staining for surfactant and cytokines also will be done.

Project C

We continued our studies on ultrafine particle effects induced by different modes of administration to the respiratory tract. In particular, we questioned the usefulness of bolus-type delivery (intratracheal instillation; oro-pharyngeal aspiration) of collected ambient PM to assess their potential to induce pulmonary injury. We hypothesize that the high dose, unrealistic rate of particle delivery associated with bolus-type delivery overwhelms local defenses in the respiratory tract resulting in an acute inflammatory response and altered biokinetics of the administered particles. In contrast, we expected when the same dose is deposited by inhalation (low, realistic dose rate) that responses will be significantly lower, or even not increase, compared to controls.

To test this hypothesis, we performed a proof-of-principle study and used ultrafine TiO2 particles (~25 nm primary particle size) as surrogate particles. We deposited 200 µg in the lower respiratory tract of rats either by intratracheal instillation or by 4 hrs whole-body inhalation.  For instillation delivery, PM material often is dispersed in saline by using a surfactant and by ultrasonication treatment to avoid the formation of large agglomerates. Thus, the instillation dosing was carried out in two groups of rats, one with ultrafine TiO2 dispersed just in normal saline alone, and the other in saline with the addition of DPPC (dipalmitoylphosphatidylcholine, a major component of lung surfactant)/albumin as dispersant.  Hydronamic particle size in the instillate were ~1.3 µm in saline and ~0.5 µm in the DPPC/albumin-saline solution. The TiO2  aerosol was generated by a screw-feeding and jet mill system and had a mass median aerodynamic diameter of 0.9 µm with a GSD of 2.2.

The resulting inflammatory response 24 hrs post-exposure showed significant differences as determined by the appearance of neutrophils in the lung lavage fluid:  31% and 24% after 200 µg TiO2 instillation in saline and in DPPC/albumin, respectively, and only 6% after a 4-hr inhalation (~200 µg deposited) of ultrafine TiO2 (Fig. 1).

In order to assess the response to inhaled TiO2  with an even lower dose rate, a 4x4 hr inhalation (4 consecutive days) was performed at 12.5 mg/m3, which resulted in a lung burden of 200 µg on day 4.  The PMN response assessed by lung lavage analysis (1.3%) was not different from control animals (1.0%).  Expressing the lavage PMB response as a function of the delivered dose rate for pristine (not coated) ultrafine TiO2 (saline dispersed and aerosol group) shows a strong impact of dose delivery rate on the response (Fig. 2). These results suggest that results from bolus-type delivery of material to the respiratory tract have to be interpreted with caution when used for risk assessment purposes. In particular, high dose rate induced mechanisms are not operating in real-world inhalation exposures. While results from bolus type administration of PM are probably still useful for toxicity ranking, when a wide range of doses is tested, they cannot be used for quantitative risk assessment.

 

 
 

Figure 1: Intratracheal instillation of ultrafine TiO(~25 nm) in rats results in significantly greater inflammatory response 24 hrs post-exposure compared to the same dose deposited during a 4 hr inhalation. There was no inflammatory response after depositing the same dose over 4 days (4 hrs of lower concentration each day).

 
 
 
Figure 2: The inflammatory response as a function of the deposited dose rate of ultrafine TiOparticles implies that underlying mechanisms are very different between bolus type delivery and realistic inhalation.

Future Activities:

Project B

Balb C and NRF 2-/- mice will be exposed to concentrated ambient particles (CAPS) and 0.3 PPM Ozone mixture or vehicle (filtered air) from postnatal days 4-7 and 10-13 for 4 hours/day. Mice will be allowed to age until 26 weeks of age and will then be re-challenge with CAPs  and 0.3PPM ozone or vehicle. Mice will be exposed for 4 consecutive days for 4 hours a day and then examined 24 hours post-exposure.

C57Bl6 mice will be exposed to concentrated ambient particles (CAPS) mixed with 0.3PPM ozone, CAPs, Ozone or vehicle (filtered air) from postnatal days 4-7 and 10-13 for 4 hours/day. Mice will be either re-challenged with CAPS, ozone, CAPs + ozone or vehicle for 4 consecutive days/ 4 hours a day and then examined 24 hours post exposure. A second group of mice will be challenged with Influenza virus and examined at 7 and 14 days post inoculation.

Project C

Evaluation of underlying mechanisms for differences in response between instillation and inhalation.


Journal Articles on this Report : 43 Displayed | Download in RIS Format

Other subproject views: All 62 publications 49 publications in selected types All 43 journal articles
Other center views: All 190 publications 156 publications in selected types All 143 journal articles
Type Citation Sub Project Document Sources
Journal Article Beckett WS, Chalupa DF, Pauly-Brown A, Speers DM, Stewart JC, Frampton MW, Utell MJ, Huang L-S, Cox C, Zareba W, Oberdorster G. Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults:a human inhalation study. American Journal of Respiratory and Critical Care Medicine 2005;171(10):1129-1135. R832415 (2010)
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  • Journal Article Berger A, Zareba W, Schneider A, Ruckerl R, Ibald-Mulli A, Cyrys J, Wichmann HE, Peters A. Runs of ventricular and supraventricular tachycardia triggered by air pollution in patients with coronary heart disease. Journal of Occupational and Environmental Medicine 2006;48(11):1149-1158. R832415 (2010)
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  • Journal Article Bruske I, Hampel R, Socher MM, Ruckerl R, Schneider A, Heinrich J, Oberdorster G, Wichmann H-E, Peters A. Impact of ambient air pollution on the differential white blood cell count in patients with chronic pulmonary disease. Inhalation Toxicology 2010;22(3):245-252. R832415 (2010)
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  • Journal Article Chalupa DC, Morrow PE, Oberdorster G, Utell MJ, Frampton MW. Ultrafine particle deposition in subjects with asthma. Environmental Health Perspectives 2004;112(8):879-882. R832415 (2010)
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  • Journal Article Couderc JP, Elder ACP, Cox C, Zareba W, Oberdorster G. Limitations of power-spectrum and time-domain analysis of heart rate variability in short-term ECG recorded using telemetry in unrestrained rats. Computers in Cardiology 2002;29:589-592. R832415 (2010)
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  • Journal Article Daigle CC, Chalupa DC, Gibb FR, Morrow PE, Oberdorster G, Utell MJ, Frampton MW. Ultrafine particle deposition in humans during rest and exercise. Inhalation Toxicology 2003;15(6):539-552. R832415 (2010)
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  • Journal Article Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein J, Oberdorster G. Systemic interactions between inhaled ultrafine particles and endotoxin. Annals of Occupational Hygiene 2002;46(Suppl 1):231-234. R832415 (2011)
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  • Journal Article Elder ACP, Gelein R, Azadniv M, Frampton M, Finkelstein J, Oberdorster G. Systemic effects of inhaled ultrafine particles in two compromised, aged rat strains. Inhalation Toxicology 2004;16(6-7):461-471. R832415 (2010)
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  • Journal Article Elder ACP, Gelein R, Oberdorster G, Finkelstein J, Notter R, Wang Z. Efficient depletion of alveolar macrophages using intratracheally inhaled aerosols of liposome-encapsulated clodronate. Experimental Lung Research 2004;30(2):105-120. R832415 (2010)
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  • Journal Article Elder A, Gelein R, Finkelstein J, Phipps R, Frampton M, Utell M, Kittelson DB, Watts WF, Hopke P, Jeong C-H, Kim E, Liu W, Zhao W, Zhuo L, Vincent R, Kumarathasan P, Oberdorster G. On-road exposure to highway aerosols. 2. Exposures of aged, compromised rats. Inhalation Toxicology 2004;16(Suppl 1):41-53. R832415 (2010)
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  • Journal Article Elder A, Johnston C, Gelein R, Finkelstein J, Wang Z, Notter R, Oberdorster G. Lung inflammation induced by endotoxin is enhanced in rats depleted of alveolar macrophages with aerosolized clodronate. Experimental Lung Research 2005;31(6):527-546. R832415 (2010)
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  • Journal Article Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, Potter R, Maynard A, Ito Y, Finkelstein J, Oberdorster G. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environmental Health Perspectives 2006;114(8):1172-1178. R832415 (2010)
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  • Journal Article Elder A, Couderc J-P, Gelein R, Eberly S, Cox C, Xia X, Zareba W, Hopke P, Watts W, Kittelson D, Frampton M, Utell M, Oberdorster G. Effects of on-road highway aerosol exposures on autonomic responses in aged, spontaneously hypertensive rats. Inhalation Toxicology 2007;19(1):1-12. R832415 (2010)
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  • Journal Article Fanning EW, Froines JR, Utell MJ, Lippmann M, Oberdorster G, Frampton M, Godleski J, Larson TV. Particulate Matter (PM) Research Centers (1999-2005) and the role of interdisciplinary center-based research. Environmental Health Perspectives 2009;117(2):167-174. R832415 (2010)
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  • Journal Article Frampton MW, Stewart JC, Oberdorster G, Morrow PE, Chalupa D, Pietropaoli AP, Frasier LM, Speers DM, Cox C, Huang L-S, Utell MJ. Inhalation of ultrafine particles alters blood leukocyte expression of adhesion molecules in humans. Environmental Health Perspectives 2006;114(1):51-58. R832415 (2010)
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  • Journal Article Han X, Gelein R, Corson N, Wade-Mercer P, Jiang J, Biswas P, Finkelstein JN, Elder A, Oberdorster G. Validation of an LDH assay for assessing nanoparticle toxicity. Toxicology 2011;287(1-3):99-104. R832415 (2011)
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  • Journal Article Hildebrandt K, Ruckerl R, Koenig W, Schneider A, Pitz M, Heinrich J, Marder V, Frampton M, Oberdorster G, Wichmann HE, Peters A. Short-term effects of air pollution: a panel study of blood markers in patients with chronic pulmonary disease. Particle and Fibre Toxicology 2009;6:25. R832415 (2009)
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  • Journal Article Kittelson DB, Watts WF, Johnson JP, Remerowki ML, Ische EE, Oberdorster G, Gelein RM, Elder A, Hopke PK, Kim E, Zhao W, Zhou L, Jeong C-H. On-road exposure to highway aerosols. 1. Aerosol and gas measurements. Inhalation Toxicology 2004;16(Suppl 1):31-39. R832415 (2010)
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  • Journal Article Kreyling WG, Semmler M, Erbe F, Mayer P, Takenaka S, Schulz H, Oberdorster G, Ziesenis A. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. Journal of Toxicology and Environmental Health-Part A 2002;65(20):1513-1530. R832415 (2010)
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  • Journal Article Lippmann M, Frampton M, Schwartz J, Dockery D, Schlesinger R, Koutrakis P, Froines J, Nel A, Finkelstein J, Godleski J, Kaufman J, Koenig J, Larson T, Luchtel D, Liu L-JS, Oberdorster G, Peters A, Sarnat J, Sioutas C, Suh H, Sullivan J, Utell M, Wichmann E, Zelikoff J. The U.S. Environmental Protection Agency Particulate Matter Health Effects Research Centers Program: a midcourse report of status, progress, and plans. Environmental Health Perspectives 2003;111(8):1074-1092. R832415 (2010)
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  • Journal Article Oberdorster G. Pulmonary effects of inhaled ultrafine particles. International Archives of Occupational and Environmental Health 2001;74(1):1-8. R832415 (2010)
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  • Journal Article Oberdorster G, Utell MJ. Ultrafine particles in the urban air:to the respiratory tract—and beyond? Environmental Health Perspectives 2002;110(8):A440-A441. R832415 (2010)
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  • Journal Article Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, Kreyling W, Cox C. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. Journal of Toxicology and Environmental Health, Part A: Current Issues 2002;65(20):1531-1543. R832415 (2010)
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  • Journal Article Oberdorster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, Cox C. Translocation of inhaled ultrafine particles to the brain. Inhalation Toxicology 2004;16(6-7):437-445. R832415 (2010)
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  • Journal Article Oberdorster G, Oberdorster E, Oberdorster J. Nanotoxicology:an emerging discipline evolving from studies of ultrafine particles. Environmental Health Perspectives 2005;113(7):823-839. R832415 (2010)
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  • Journal Article Oberdorster G, Stone V, Donaldson K. Toxicology of nanoparticles: a historical perspective. Nanotoxicology 2007;1(1):2-25. R832415 (2007)
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  • Journal Article Oberdorster G, Elder A, Rinderknecht A. Nanoparticles and the brain: cause for concern? Journal of Nanoscience and Nanotechnology 2009;9(8):4996-5007. R832415 (2009)
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  • Journal Article Oberdorster G. Safety assessment for nanotechnology and nanomedicine: concepts of nanotoxicology. Journal of Internal Medicine 2010;267(1):89-105. R832415 (2009)
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  • Journal Article Pietropaoli AP, Frampton MW, Hyde RW, Morrow PE, Oberdorster G, Cox C, Speers DM, Frasier LM, Chalupa DC, Huang L-S, Utell MJ. Pulmonary function, diffusing capacity, and inflammation in healthy and asthmatic subjects exposed to ultrafine particles. Inhalation Toxicology 2004;16(Suppl 1):59-72. R832415 (2010)
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  • Journal Article Pui DYH, Qi C, Stanley N, Oberdorster G, Maynard A. Recirculating air filtration significantly reduces exposure to airborne nanoparticles. Environmental Health Perspectives 2008;116(7):863-866. R832415 (2007)
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  • Journal Article Riesenfeld E, Chalupa D, Gibb FR, Oberdo G, Gelein R, Morrow PE, Utell MJ, Frampton MW. Ultrafine particle concentrations in a hospital. Inhalation Toxicology 2000;12(Suppl 2):83-94. R832415 (2010)
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  • Journal Article Ruckerl R, Phipps RP, Schneider A, Frampton M, Cyrys J, Oberdorster G, Wichmann HE, Peters A. Ultrafine particles and platelet activation in patients with coronary heart disease – results from a prospective panel study. Particle and Fibre Toxicology 2007;4:1. R832415 (2010)
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  • Journal Article Rushton EK, Jiang J, Leonard SS, Eberly S, Castranova V, Biswas P, Elder A, Han X, Gelein R, Finkelstein J, Oberdorster G. Concept of assessing nanoparticle hazards considering nanoparticle dosemetric and chemical/biological response metrics. Journal of Toxicology and Environmental Health, Part A 2010;73(5-6):445-461. R832415 (2010)
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  • Journal Article Schneider A, Hampel R, Ibald-Mulli A, Zareba W, Schmidt G, Schneider R, Ruckerl R, Couderc JP, Mykins B, Oberdorster G, Wolke G, Pitz M, Wichmann H-E, Peters A. Changes in deceleration capacity of heart rate and heart rate variability induced by ambient air pollution in individuals with coronary artery disease. Particle and Fibre Toxicology 2010;7:29 (12 pp.). R832415 (2011)
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  • Journal Article Semmler-Behnke M, Takenaka S, Fertsch S, Wenk A, Seitz J, Mayer P, Oberdorster G, Kreyling WG. Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent reentrainment onto airways epithelium. Environmental Health Perspectives 2007;115(5):728-733. R832415 (2007)
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  • Journal Article Silva VM, Corson N, Elder A, Oberdorster G. The rat ear vein model for investigating in vivo thrombogenicity of ultrafine particles (UFP). Toxicological Sciences 2005;85(2):983-989. R832415 (2010)
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  • Journal Article Su Y, Sipin MF, Prather KA, Gelein RM, Lunts A, Oberdorster G. ATOFMS characterization of individual model aerosol particles used for exposure studies. Aerosol Science and Technology 2005;39(5):400-407. R832415 (2010)
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  • Journal Article Su Y, Sipin MF, Spencer MT, Qin X, Moffet RC, Shields LG, Prather KA, Venkatachari P, Jeong C-H, Kim E, Hopke PK, Gelein RM, Utell MJ, Oberdorster G, Berntsen J, Devlin RB, Chen LC. Real-time characterization of the composition of individual particles emitted from ultrafine particle concentrators. Aerosol Science and Technology 2006;40(6):437-455. R832415 (2010)
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  • Journal Article Veranth JM, Gelein R, Oberdorster G. Vaporization – condensation generation of ultrafine hydrocarbon particulate matter for inhalation toxicology studies. Aerosol Science and Technology 2003;37(7):603-609. R832415 (2010)
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  • Journal Article Yue W, Schneider A, Stolzel M, Ruckerl R, Cyrys J, Pan X, Zareba W, Koenig W, Wichmann H-E, Peters A. Ambient source-specific particles are associated with prolonged repolarization and increased levels of inflammation in male coronary artery disease patients. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 2007;621(1-2):50-60. R832415 (2010)
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  • Journal Article Yue W, Schneider A, Ruckerl R, Koenig W, Marder V, Wang S, Wichmann H-E, Peters A, Zareba W. Relationship between electrocardiographic and biochemical variables in coronary artery disease. International Journal of Cardiology 2007;119(2):185-191. R832415 (2010)
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  • Journal Article Zareba W, Nomura A, Couderc JP. Cardiovascular effects of air pollution:what to measure in ECG? Environmental Health Perspectives 2001;109(Suppl 4):533-538. R832415 (2010)
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  • Journal Article Zareba W, Couderc JP, Oberdorster G, Chalupa D, Cox C, Huang L-S, Peters A, Utell MJ, Frampton MW. ECG parameters and exposure to carbon ultrafine particles in young healthy subjects. Inhalation Toxicology 2009;21(3):223-233. R832415 (2008)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, particulate matter, Toxicology, Health Risk Assessment, Risk Assessments, Physical Processes, atmospheric particulate matter, atmospheric particles, acute cardiovascular effects, airway disease, exposure, animal model, ambient particle health effects, atmospheric aerosol particles, ultrafine particulate matter, PM, inhalation toxicology, cardiovascular disease

    Progress and Final Reports:

    Original Abstract
  • 2006 Progress Report
  • 2007 Progress Report
  • 2008 Progress Report
  • 2009 Progress Report
  • 2010 Progress Report
  • Final Report

  • Main Center Abstract and Reports:

    R832415    Rochester PM Center

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832415C001 Characterization and Source Apportionment
    R832415C002 Epidemiological Studies on Extra Pulmonary Effects of Fresh and Aged Urban Aerosols from Different Sources
    R832415C003 Human Clinical Studies of Concentrated Ambient Ultrafine and Fine Particles
    R832415C004 Animal models: Cardiovascular Disease, CNS Injury and Ultrafine Particle Biokinetics
    R832415C005 Ultrafine Particle Cell Interactions In Vitro: Molecular Mechanisms Leading To Altered Gene Expression in Relation to Particle Composition