Final Report: Project 1 -- Pulmonary Metabolic Response

EPA Grant Number: R832414C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R832414
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: San Joaquin Valley Aerosol Health Effects Research Center (SAHERC)
Center Director: Wexler, Anthony S.
Title: Project 1 -- Pulmonary Metabolic Response
Investigators: Fanucchi, Michelle V. , Buckpitt, Alan , Plopper, Charles , Winkle, Laura Van
Institution: University of California - Davis
EPA Project Officer: Chung, Serena
Project Period: October 1, 2005 through September 30, 2010 (Extended to September 30, 2011)
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Health Effects , Air

Objective:

To determine whether the increased pulmonary vulnerability to polycyclic aromatic hydrocarbons (PAHs) in neonates is exacerbated when PAH is adsorbed to particulate matter. By compromising detoxification mechanisms, particles of mixed (high PAH) composition will result in more injury than particles composed of with a low composition of PAH.

Summary/Accomplishments (Outputs/Outcomes):

Specific Aim 1: PM alone vs. PM with PAH vs. PAH alone and Specific Aim 2: PM with PAH vs. PM with low PAH

The following papers are being prepared for Specific Aims 1 and 2:

  1. re PM alone: In vivo exposures insufflation of carbon black, acetylene and ethylene soot (Fanucchi)
  2. re PAH alone: Age-specific pulmonary metabolism of 1-nitronaphthalene (Fanucchi and Plopper)
  3. re PAH alone: Alterations in extracellular nasal and pulmonary glutathione pools in adult and postnatal rat following 1-nitronapthalene exposure (Fanucchi and Buckpitt)
  4. PM with low PAH vs. PM with high PAH: Comparison of the immune response to inhaled diffusion flame vs. premixed flame soot in neonatal and adult rats (Van Winkle and Anderson)
  5. Combustion derived ultrafine particles differentially induce Cytochrome P450 1A1 and 1B1 in neonatal and adult rat lungs (Chan, Van Winkle and Buckpitt).

Papers 4 and 5 are the responsibility of the principal investigator, Dr. Van Winkle, and we expect submission within the next 2 months. The final data were delayed because students Anderson and Chan are completing these studies as part of their dissertations.

Seven papers were published for these two aims. These papers demonstrate that the conducting airway epithelium is a target for inhaled particles, even for the fine/ultrafine particles at low doses used in these studies. We further found that neonates are less able to upregulate key antioxidant enzymes in response to soot exposures and that they are more susceptible to cytotoxicity. PAH containing soot (PFP) causes more airway epithelial cytotoxicity and LDH release into BALF than soot that is low in PAHs (DFP). Interestingly, the low PAH soot had a more pronounced effect on neutrophil recruitment in the neonatal animals (Anderson, in preparation). Finally, our papers show that a key PAH in vehicle exhaust, naphthalene, has sex differences in bronchiolar epithelial repair and that trefoil factors mediate the repair processes from this toxicant.

Specific Aim 3 PM with PAH +/- ozone

Exposures have been completed for this Aim and papers are in preparation. A key difference between the exposures in this aim and the exposures in the previous aim are the increased neutrophilic recruitment to the airways by ozone. This followed a different temporal pattern in neonatal vs. adult rats.

Specific Aim 4 Seasonal urban and environmental particulate matter vs. chamber particulate matter

This aim is being addressed using in vitro approaches and then combining these data with data from the in vivo exposures conducted as part of Aim 2. The chamber particulate matter exposures have been complicated by low yield of the very small size high PAH PM (PFP). This renders in vivo studies using intratracheal instillation unfeasible. The current plan is to compare the ability of the chamber and environmental PM to generate reactive oxidant species in vitro and then also to measure the degree of induction of specific antioxidant enzymes that are responsible for detoxifying these species in the neonatal vs. adult rat lung. There are substantial differences in the responsiveness of these enzymes to PM + PAH exposure (PFP) by age.

The paper titled "Differential antioxidant expression in neonatal and adult rat lungs exposed to flame generated ultrafine particulate matter" (Chan, Charrier, Anastasio and Van Winkle) is in preparation.

Conclusions:

Overall Summary: The key findings from this project are: 1) there is elevated susceptibility as evidenced by increased toxicity in neonates vs. adults exposed to the same dose of PM; 2) the difference in susceptibility by age is accentuated when the PM contains more oily PAHs; 3) an inability of neonates to upregulate key antioxidant enzymes may contribute to their elevated susceptibility; and 4) slow, but prolonged recruitment of polymorphonuclear neutrophils (PMNs) to the lung in neonates compared to adults may contribute to altered susceptibility. Studies are ongoing, supported by other mechanisms, to more clearly relate dose delivered in neonates vs. adults to toxicity in the lung.


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

Other subproject views: All 43 publications 10 publications in selected types All 8 journal articles
Other center views: All 128 publications 71 publications in selected types All 64 journal articles
Type Citation Sub Project Document Sources
Journal Article Chan JKW, Fanucchi MV, Anderson DS, Abid AD, Wallis CD, Dickinson DA, Kumfer BM, Kennedy IM, Wexler AS, Van Winkle LS. Susceptibility to inhaled flame-generated ultrafine soot in neonatal and adult rat lungs. Toxicological Sciences 2011;124(2):472-486. R832414 (Final)
R832414C001 (Final)
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  • Journal Article Day KC, Plopper CG, Fanucchi MV. Age-specific pulmonary cytochrome P-450 3A1 expression in postnatal and adult rats. American Journal of Physiology-Lung Cellular and Molecular Physiology 2006;291(1):L75-L83. R832414 (2009)
    R832414C001 (2007)
    R832414C001 (2008)
    R832414C001 (Final)
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  • Journal Article Greeley MA, Van Winkle LS, Edwards PC, Plopper CG. Airway trefoil factor expression during naphthalene injury and repair. Toxicological Sciences 2010;113(2):453-467. R832414 (Final)
    R832414C001 (2010)
    R832414C001 (Final)
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  • Journal Article Kennedy IM. The health effects of combustion-generated aerosols. Proceedings of the Combustion Institute 2007;31(2):2757-2770. R832414 (2009)
    R832414C001 (2008)
    R832414C001 (Final)
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  • Journal Article Sutherland KM, Combs TJ, Edwards PC, Van Winkle LS. Site-specific differences in gene expression of secreted proteins in the mouse lung: comparison of methods to show differences by location. Journal of Histochemistry and Cytochemistry 2010;58(12):1107-1119. R832414 (Final)
    R832414C001 (2010)
    R832414C001 (Final)
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  • Journal Article Sutherland KM, Edwards PC, Combs TJ, Van Winkle LS. Sex differences in the development of airway epithelial tolerance to naphthalene. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;302(1):L68-L81. R832414 (Final)
    R832414C001 (Final)
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  • Journal Article Van Winkle LS, Chan JK, Anderson DS, Kumfer BM, Kennedy IM, Wexler AS, Wallis C, Abid AD, Sutherland KM, Fanucchi MV. Age specific responses to acute inhalation of diffusion flame soot particles:cellular injury and the airway antioxidant response. Inhalation Toxicology 2010;22(Suppl 2):70-83. R832414 (Final)
    R832414C001 (2010)
    R832414C001 (Final)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, Air, particulate matter, Health Risk Assessment, Environmental Chemistry, Epidemiology, Risk Assessments, ambient aerosol, lung injury, toxicology, long term exposure, lung disease, air toxics, airway disease, airborne particulate matter, endothelial function, pariculate matter, particle exposure, ultrafine particulate matter, ambient particle health effects, human exposure, epidemiological studies, PM, transport and fate

    Progress and Final Reports:

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

  • Main Center Abstract and Reports:

    R832414    San Joaquin Valley Aerosol Health Effects Research Center (SAHERC)

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R832414C001 Project 1 -- Pulmonary Metabolic Response
    R832414C002 Endothelial Cell Responses to PM—In Vitro and In Vivo
    R832414C003 Project 3 -- Inhalation Exposure Assessment of San Joaquin Valley Aerosol
    R832414C004 Project 4 -- Transport and Fate Particles
    R832414C005 Project 5 -- Architecture Development and Particle Deposition