2001 Progress 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: EPA NYU PM Center: Health Risks of PM Components
Center Director: N/A
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)
Project Period Covered by this Report: June 1, 2001 through May 31, 2002
RFA: Airborne Particulate Matter (PM) Centers (1999) RFA Text |  Recipients Lists
Research Category: Air Quality and Air Toxics , Particulate Matter , Air


The objective of this research project is to determine the role that particulate matter (PM)-associated transition metals might play in causing previously observed changes in host immunocompetence. To this end, Streptococcus pneumoniae-infected rats are exposed to artificially generated atmospheres containing soluble forms of individual metals found in immunoreactive New York City (NYC) PM samples. Similar studies will then employ mixtures of the soluble forms of the metals to ascertain whether the immunosuppression in PM-exposed hosts is dependent, at least in part, on any interactions between the metals present. Immunotoxic effects of metal exposure on noninfected animals also are examined in these studies to determine the extent to which the PM-associated metals are capable of producing immunodysfunction in and of themselves.

Progress Summary:

Studies employing uninfected 8-month-old F-344 rats examined the immunological, histological, and biochemical changes associated with a single 5-hour (nose-only) inhalation exposure to soluble chloride salts of Fe, Ni, Mn, and Cu at a concentration of approximately 80 µg/m3. Effects were examined 1, 18, and 48 hours postmetal exposure. Except for Ni, no metal-induced alterations were observed upon lavaged cell profile, viability, cell number, or lavageable lactate dehydrogenase (LDH)/protein levels. In some cases, circulating percentages of neutrophils, lymphocytes, and monocytes were altered 1 hour postexposure, by18 hours postexposure, differential blood counts returned to control levels. This time-related response is identical to that as seen in our earlier NYC PM studies and may indicate a particle-induced stress response. Although exposure to Mn or Cu had no effects on either local or systemic immune parameters, inhalation of Ni (either alone or in combination with Cu) enhanced splenic T-lymphocyte proliferative responses 18 hours postexposure. Conversely, proliferation of splenic T-lymphocytes was decreased in Fe-exposed animals (compared to the control). These results demonstrate the ability of inhaled immunotoxic metals at a low dose to alter systemic immunity. In addition, superoxide anion (O2·-) production by macrophages (Mø) recovered from Fe-exposed rats was enhanced compared to production from control cells. Effects on hydrogen peroxide (H2O2) production by Mø were dependent on time post-exposure.

In another series of studies, rats were infected with S. pneumoniae 48 hours prior to exposure to either air or soluble metal chloride either alone or in combination. Rats were sacrificed either just before the initiation of exposure or 18 hours later and then effects on circulating blood cell profile and pulmonary bacterial burdens were determined. Infected animals exposed for 5 hours to Fe and examined 18 hours later had a 37 percent increase in blood neutrophils and a 33 percent drop in lymphocytes (compared to air controls). Moreover, although virtually all bacteria were cleared from the lungs of infected air-exposed rats by 48 hours post-infection, bacterial burdens in Fe-exposed animals were increased 10,000-fold compared to those rats sacrificed immediately prior to exposure (see Figure 1). However, because S. pneumoniae are iron-sequestering organisms, it is difficult to determine whether Fe-induced changes in burdens were due to the effects on the bacteria itself, to alterations in immune mechanisms responsible for the clearance of the pathogen, or a combination of both factors. In another experiment in which already-infected rats were examined 3 and 18 hours following Fe exposure, percentages of blood neutrophils were significantly reduced (compared to control) 3 hours following exposure, but returned to control values by 18 hours.

Figure 1. Burdens of Streptococcus Pneumoniae in the Lungs

S. pneumoniae-infected rats exposed to MnCl2 for 5 hours and sacrificed 18 hours postexposure had a greater increase in bacterial killing/clearance (as compared to the control). Because of the antibacterial properties of some forms of Mn, it is unknown whether changes in bacterial burdens were due to direct effects on the pathogen, Mn-induced alterations in antimicrobial immune defense mechanisms, or a combination of both factors. In addition, infected rats exposed subsequently for 5 hours to approximately 80 µg NiCl2 demonstrated a significantly reduced ability to clear bacteria from the lung 18 hours postexposure (compared to the time-matched air control) (see Figure 2). Nickel is a potent immunosuppressant in mammalian systems and has been shown to depress Mø function following the inhalation of soluble Ni at higher doses. Alterations in pulmonary Mø antimicrobial activity may be responsible for the observed effects on bacterial clearance. Overall, studies demonstrate that acute inhalation of ambient PM less than or equal to 2.5 µm can worsen the outcome of an ongoing pulmonary infection, and that associated Fe, and possibly Ni, play a role in this immunotoxicity.

Figure 2. S. pneumoniae-Infected Rats Exposed for 5 Hours to Approximately 80 µg NiCl2

Future Activities:

Studies examining the effects of lower (more PM-relevant) concentrations of only those metals having effects at 80 µg/m3 on host antimicrobial defense mechanisms (i.e., Fe and Ni) will be performed. In addition, studies will assess the effects of insoluble salts of these same five metals (Fe, Mn, Ni, Zn, and Cu), alone and in combination, to determine whether it is the soluble or insoluble metal forms that play the most important role in particle-induced effects on antimicrobial lung defenses.

Journal Articles on this Report : 1 Displayed | Download in RIS Format

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
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
  • Supplemental Keywords:

    particulate matter, PM, exposure, animal, rat, toxicology, metal, pneumonia, Streptococcus pheumoniae, immunotoxic., RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, ENVIRONMENTAL MANAGEMENT, particulate matter, Toxicology, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Analytical Chemistry, Environmental Monitoring, Physical Processes, 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

    Progress and Final Reports:

    Original Abstract
  • 1999 Progress Report
  • 2000 Progress Report
  • 2002 Progress Report
  • 2003 Progress Report
  • 2004
  • Final Report

  • Main Center Abstract and Reports:

    R827351    EPA NYU PM Center: Health Risks of PM Components

    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 PM2.5
    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 PM2.5 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 PM2.5
    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