Grantee Research Project Results

Final Report: Role of PM-Associated Transition Metals in Exacerbating Infectious Pneumoniae in Exposed Rats

EPA Grant Number: R827351C007
Subproject: this is subproject number 007 , established and managed by the Center Director under grant R827351
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Health Effects Institute (2000 — 2005)
Center Director: Greenbaum, Daniel S.
Title: Role of PM-Associated Transition Metals in Exacerbating Infectious Pneumoniae in Exposed Rats
Investigators: Zelikoff, Judith T.
Institution: New York University School of Medicine
EPA Project Officer: Chung, Serena
Project Period: June 1, 1999 through May 31, 2005 (Extended to May 31, 2006)
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text | Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air

Objective:

Soluble metals selected for study including Zn, Fe, Cu, Ni, and Mn were based upon those immunomodulating metals identified from filters collected during the original New York City (NYC) study. In the first sets of studies, rats were exposed to a single metal at a concentration of 100 μg/m³. A dose substantially higher than that found on the original particulate matter (PM) atmosphere was selected so as to eliminate those metals having no effect on bacterial host resistance. Iron, Zn, and Ni proved most biologically active in this capacity. In addition to host resistance, a number of immune parameters important for resistance of the host against infectious bacterial pathogens were also evaluated. These included: pulmonary histology; lung cell numbers and profiles; lavageable lactate dehydrogenase activity; total protein levels and cytokines; macrophage-mediated production of reactive oxygen species; splenic lymphocyte proliferation; and circulating blood cell profiles. Even at this relatively high metal dose, inhalation of either Cu or Mn had little or no effects on these particular immune parameters. Similar to that observed for host resistance, Zn, Fe, and Ni, had the greatest effects on these biological endpoints. Based upon these results, only these three metals were evaluated at more relevant concentrations. In this case, only Fe and Ni altered host resistance at a 10-fold lower concentration (i.e., 10 μg/m³); Fe compromised pulmonary bacterial clearance by about 60, while exposure to 10 μg Ni/m³ actually enhanced clearance by ~30%. Given that PM-associated metals do not exist in isolation, the biological effects of exposure to PM likely depend upon responses to metals in combination, and that exposure to pollutant combinations often results in responses different from those seen following inhalation of individual materials, mixture studies were performed to examine the interactive toxicity of Zn, Ni, and Fe on anti-bacterial defense mechanisms and the “handling” of ongoing pneumococcal infections. At an equimolar metal concentration of 50 μg/m³, rats were exposed simultaneously to Cu plus Ni, Zn plus Ni, or Fe plus Mn. Both Cu and Mn significantly antagonized the pulmonary toxicity of Ni and Fe, respectively. On the other hand, exposure to Zn acted to reverse the “beneficial” effects of Ni alone on pulmonary bacterial clearance; simultaneous exposure of Zn and Ni reduced clearance of Streptococcus by about 30%.

Summary/Accomplishments (Outputs/Outcomes):

Previous investigations in this laboratory demonstrated that a single 5 hr inhalation exposure of Streptococcus pneumoniae-infected male rats to concentrated ambient PM_2.5 from New York City (NYC) air [at concentrations approximating or greater than the promulgated 24 hr National Ambient Air Quality Standard (NAAQS) for PM_2.5 (~65 - ~150 vs. 50 μg/m³, respectively)], altered both pulmonary and systemic immunity, as well as exacerbated the infection process, in a time- post-exposure-dependent manner. These New York University (NYU)-PM Center-supported studies were performed to correlate metal content of ambient PM_2.5 with its in vivo immunotoxicity so as to identify and characterize the role of constitutive transition metals for exacerbating ongoing S. pneumoniae infections. The central hypothesis of this particular component was that metals (either individually or in combination) associated with inhaled NYC particulates influenced the severity and/or kinetics of pulmonary bacterial clearance induced by concentrated ambient NYC PM_2.5. By exposing rats previously-infected with Streptococcus pneumoniae (i.e., 48 hr prior to PM exposure) to PM-associated soluble metals, at doses representative of those within the original intact parental PM atmosphere, metals that influence the ability of PM to alter host resistance against infectious agents could be defined. A single major objective was addressed: to ascertain which transition metals (either individually or in combination) found most active in the previously identified portion of ambient PM play significant roles in exacerbating ongoing pneumococcal-induced pneumonia in PM-exposed hosts.

Soluble metals selected for study included zinc (Zn), iron (Fe), copper (Cu), nickel (Ni), and manganese (Mn), which were based upon those immunomodulating metals identified by XRF analyses and atomic absorption spectroscopy from filters collected during the original NYC study. For the first sets of studies, rats were exposed by inhalation (nose-only) to a single metal at a concentration of 100 μg/m³. A dose substantially higher than that found on the original PM atmosphere was selected so as to eliminate those metals having no effect on bacterial host resistance.

Conclusions:

These studies demonstrated that even an acute (5 hr) exposure to PM-associated metals including soluble Fe, Zn, and Ni act to exacerbate an ongoing S. pneumoniae infection in particle-exposed rats. Moreover, these same metals in combination can produce responses different from those seen following inhalation of the individual metals alone. This study has provided necessary information as to the particular PM constituents/metal interactions responsible for the observed effects upon host immunocompetence. Taken together, results of these investigations provide biological plausibility for the role of certain PM-associated transition metals to worsen the outcome of an ongoing pulmonary infection.

Technical Report:

Long Version of Final Report (PDF) (3 pp, 28.5 K, About PDF)

Journal Articles on this Report : 2 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 3 publications	2 publications in selected types	All 2 journal articles
Other center views:	All 112 publications	101 publications in selected types	All 89 journal articles

Publications
Type	Citation	Sub Project	Document Sources
Journal Article	Zelikoff JT, Schermerhorn KR, Fang K, Cohen MD, Schlesinger RB. A role for associated transition metals in the immunotoxicity of inhaled ambient particulate matter. Environmental Health Perspectives 2002;110(Suppl 5):871-875.	R827351 (Final) R827351C007 (2001) R827351C007 (2002) R827351C007 (Final)	Full-text from PubMed Abstract from PubMed
Journal Article	Zelikoff JT, Chen LC, Cohen MD, Fang K, Gordon T, Li Y, Nadziejko C, Schlesinger RB. Effects of inhaled ambient particulate matter on pulmonary antimicrobial immune defense. Inhalation Toxicology 2003;15(2):131-150.	R827351 (Final) R827351C007 (2003) R827351C007 (Final)	Abstract from PubMed Full-text: Berkeley-Full Text PDF Exit Abstract: Taylor and Francis-Abstract Exit

Supplemental Keywords:

immune mechanisms, infection,, RFA, Health, PHYSICAL ASPECTS, Scientific Discipline, Air, ENVIRONMENTAL MANAGEMENT, particulate matter, Toxicology, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Analytical Chemistry, Physical Processes, Environmental Monitoring, Atmospheric Sciences, Risk Assessment, ambient air quality, atmospheric particulate matter, particulates, metal absorption, air toxics, atmospheric particles, chemical characteristics, ambient air monitoring, acute cardiovascular effects, acute lung injury, airborne particulate matter, environmental risks, exposure, epidemelogy, Sulfur dioxide, air pollution, pneumonia, aerosol composition, atmospheric aerosol particles, human exposure, PM, exposure assessment

Relevant Websites:

Long Version of Final Report (PDF) (3 pp, 28.5 K, About PDF)
http://www.med.nyu.edu/environmental/ Exit
https://www.epa.gov/research-grants/

Progress and Final Reports:

Original Abstract

Main Center Abstract and Reports:

R827351 Health Effects Institute (2000 — 2005)

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R827351C001 Exposure Characterization Error
R827351C002 X-ray CT-based Assessment of Variations in Human Airway Geometry: Implications for Evaluation of Particle Deposition and Dose to Different Populations
R827351C003 Asthma Susceptibility to PM_2.5
R827351C004 Health Effects of Ambient Air PM in Controlled Human Exposures
R827351C005 Physicochemical Parameters of Combustion Generated Atmospheres as Determinants of PM Toxicity
R827351C006 Effects of Particle-Associated Irritants on the Cardiovascular System
R827351C007 Role of PM-Associated Transition Metals in Exacerbating Infectious Pneumoniae in Exposed Rats
R827351C008 Immunomodulation by PM: Role of Metal Composition and Pulmonary Phagocyte Iron Status
R827351C009 Health Risks of Particulate Matter Components: Center Service Core
R827351C010 Lung Hypoxia as Potential Mechanisms for PM-Induced Health Effects
R827351C011 Urban PM_2.5 Surface Chemistry and Interactions with Bronchoalveolar Lavage Fluid (BALF)
R827351C012 Subchronic PM2.5 Exposure Study at the NYU PM Center
R827351C013 Long Term Health Effects of Concentrated Ambient PM_2.5
R827351C014 PM Components and NYC Respiratory and Cardiovascular Morbidity
R827351C015 Development of a Real-Time Monitoring System for Acidity and Soluble Components in Airborne Particulate Matter
R827351C016 Automated Real-Time Ambient Fine PM Monitoring System

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