Grantee Research Project Results

2010 Progress Report: The Chemical Properties of PM and their Toxicological Implications

EPA Grant Number: R832413C003
Subproject: this is subproject number 003 , 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: The Chemical Properties of PM and their Toxicological Implications
Investigators: Cho, Arthur K. , Froines, John R.
Current Investigators: Cho, Arthur K. , Froines, John R. , Harkema, Jack , Fukuto, Jon , Kumagai, Yoshito
Institution: University of California - Los Angeles
Current Institution: University of California - Los Angeles , Michigan State University , University of Tsukuba
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: August 1, 2009 through July 31,2010
RFA: Particulate Matter Research Centers (2004) RFA Text |  Recipients Lists
Research Category: Human Health , Air

Objective:

The objective of the research in project 3 is to characterize the chemical properties of air pollutants that relate to their effects on cells and intact organisms. By relating these chemical properties to biological effects, simple chemical assays can be used to predict the potential hazards of air pollutants. However, chemical properties alone will not predict potential health hazards, as the physical state of the pollutant will dictate its tissue distribution and cellular access. Thus, in addition to particles of varying sizes, exposure includes vapor phase components which, while generally ignored, include reactive chemicals as well. Accordingly, we have collected and examined particles and vapors from the same air mass, focusing on the organic components of the vapor phase and metals and organic species in the particle phase.

Progress Summary:

1. Rationale/hypothesis

Biological effects of airborne particulate matter (PM) are due directly or indirectly to chemical reactions involving their chemical components. These chemical components can initiate cellular effects by acting as prooxidants, which catalyze formation of reactive oxygen species (ROS) or as electrophiles, substances capable of forming covalent bonds with functional groups on biological molecules such as proteins, peptides and nucleic acids.

To test the hypothesis, a group of assays were developed that provide quantitative values for the presence of quinones and for the capacity of a given sample to carry out prooxidant and electrophilic reactions.

2. Assays developed and their application

Quinones have been found to be particularly useful as prototypical organic compounds with prooxidant and electrophilic activity, and are present in ambient air and diesel exhaust. Selected polycyclic aromatic hydrocarbons (PAHs) and quinones (1,2- and 1,4- naphthoquinone, 9,10-phenanthroquinone and 9,10-anthroquinone) were measured by project 3 personnel (Cho, et al., 2004). Although this assay does not measure all of the quinones present (for example, see Jakober, et al., 2006), they provide useful quantitative data on quinone presence. Air pollutant mixtures also were analyzed for iron and copper content by IPC-MS by the Chemistry Department Analytical Service. Assays for prooxidants utilized dithiothreitol (DTT) based, redox activity (Cho, et al., 2005) based and Fenton reaction based dihydroxybenzoate (DHBA) formation (DiStefano, et al., 2009). The DTT assay result provides a summary of both organic and metal based activity, with metal based activity inhibited by the metal chelator, DTPA, whereas the DHBA assay result is based solely on metals catalyzing the Fenton reaction.

The inactivation ofglyceraldehyde-3-phosphate dehydrogenase (GAPDH) by air pollutant mixtures (Rodriguez, et al., 2004; Shinyashiki, et al., 2009) is used to assess the levels of electrophilies in the samples. These assays have been used to characterize particle and vapor samples collected at multiple sites and conditions and under different conditions to provide quantitative data useful in addressing the questions related to the hypothesis above and to hypotheses developed by other projects.

3. Toxicokinetic issues and physical properties

The physical properties of the reactive chemical species in air pollution mixtures are important concerns in exposure because they control the toxicokinetics of these species. Air pollutant particles collected in the Los Angeles Basin appear to have a coating of organic substances and reactive metals with the content varying with the size of the particles(Ntziachristos, et al., 2007). Much of these adsorbed chemical species are dissociable in aqueous or polar organic media so the particles can be viewed as a carrier for these reactive species (Li, et al., 2003). Upon inhalation, the particles can move to different sites in the pulmonary system where they and their associated coatings can attach to the lipid membranes of cells, or enter cells by phagocytotic processes and release their boundmaterials intracellularly. The volatile species enter the lungs as a gas, which dissolves in the lung lining fluid, allowing a rapid and extensive distribution over the lung lining. The solubilized chemicals, as solutes in the lung lining fluid, will interact with cells over a large area. However, ultra fine particles enter cells directly and can present high levels of the adsorbed chemicals to an individual cell. These issues prompted us to investigate the distribution of prooxidants and electrophiles in air pollution mixtures as well as the actual concentrations.

4. Results

We postulate that the organic chemical species contributing to prooxidant and electrophilic activity include quinones present in gaseous and particle phases of air pollutant mixtures as products of fossil fuel combustion. Chemical assays of diesel exhaust particles (DEP) and ambient air samples have supported this hypothesis (Cho, et al., 2004) and we have examined air samples from different sites and collected under different conditions to assess the nature of the variability. Numerous studies have suggested that the prevailing wind conditions in the Los Angeles Basin result in an increase in photochemically generated reactive chemical species capable of initiating adverse cellular effects as a given air mass moves across the Basin.

Quinones as prototypical reactive chemical components of air pollutants

Quinones are formed as products of fossil fuel combustion and as photochemical reaction products of precursor polycyclic aromatic hydrocarbons (PAHs). This group of organic compounds has been particularly useful in our studies as prototypical organic compounds with prooxidant and electrophilic activity. They exhibit both prooxidant and electrophilic properties under conditions relevant to cellular events, i.e., in aqueous media and at physiological pH (Rodriguez, et al., 2004). For this reason, many of our approaches and methodologies have reflected or have precedents in experiments with quinones. We have used 9,10-phenanthroquinone (PQ), a prooxidant, 1,4-benzoquinone (BQ) , an electrophile and 1,2-naphthoquinone (1,2-NQ), which has both prooxidant and electrophilic properties, in these studies (Rodriguez, et al., 2004). All three quinones have been found in ambient air samples and interact with cellular systems, indicating that they have ready access to cytoplasmic targets. Both PQ and 1,2-NQ have DTT activity, but BQ does not and these properties were useful in the development of the DTT base prooxidant assay. Both 1,2-NQ (Iwamoto, et al., 2007b) and BQ (Rodriguez, et al., 2004) will inactivate GAPDH bycovalent bond formation, but PQ will not. In tissue studies, 1,2-NQ has been shown to cause the contraction of pulmonary smooth muscle through electrophilic inactivation of protein tyrosine phosphatase 1B, a regulatory protein of epidermal growth factor receptor, a receptor system involved in cell proliferation and in components of the inflammatory response (Kikuno, et al., 2006; Iwamoto, et al., 2007b). The last study (Iwamoto, et al.,2007b) has provided targets for the evaluation of the electrophiles present in ambient air.

Formation of quinones

To test the notion that photochemical reactions contribute to quinone formation, concentrations of particle bound 9,10-phenanthroquinone (PQ), a highly reactive prooxidant (Taguchi, et al., 2008), were monitored in air masses at selected sites between the coast (Long Beach) and the eastern end of the Basin, Riverside. The collections were made attimes corresponding to the movement of air across the basin. A distance related increase in the levels of this quinone was observed as the air mass moved east. Furthermore, PQ levels were correlated with the particle phase content of its precursor PAH, phenanthrene, in the western end and correlated with the vapor phase in the eastern end of the basin, supporting the hypothesis that PQ is being formed from vapor phase phenanthrene, through photochemical reactions occurring as the air mass moves toward the eastern end of the basin (Eiguren-Fernandez, et al., 2008b). Thus, in addition to PQ formation by combustion, atmospheric photochemical reactions are generating additional quantities from its precursor, phenanthrene. Analogous reactions occur for the volatile, 1,4-naphthoquinone (Eiguren-Fernandez, et al., 2008a) as evidenced by its changes as the air mass moved east.

Distribution of quinones in particles and vapors

In studies examining the distribution of quinones and their precursor PAHs, the low molecular weight naphthoquiones were found to be mostly in the vapor phase whereas PQ was found mostly in the particle phase (Eiguren-Fernandez, et al., 2008a). The presence of naphthoquinones in the vapor phase indicates that significant concentrations of reactive components of ambient air are present in the vapors. Based on results such as these, we then began analysis of the vapors and particles for their chemical reactivity. Our first study was an assessment of the volatility of reactants associated with diesel exhaust particles (DEPs).

Physical nature of chemical reactivity in air pollutant mixtures

In a study investigating the effects of emission control devices, the exhaust of several diesel engine vehicles retrofitted with multiple devices including a thermal denuder was conducted by the USC group as part of Project 1. Thermal denuders trap organic compoundsvolatilized by the heater in the devices by activated carbon embedded in the adsorber section of the devices. At temperatures of 150 and 230^o C denuders removed >95% of all prooxidant chemicals, indicating that the DTT based prooxidants in diesel exhaust were socalled semivolatile organic compounds (Biswas, et al., 2009). These particle associated prooxidants also were water soluble because the correlation coefficient between water solubleorganics and DTT activity was 0.91.

To further evaluate the nature of the substances removed by heating at these temperatures, a sample of EPA DEP with high organic based redox and electrophilic activity was subjected to an 8 hour heating period at temperatures from room temperature to 100^o C. The residues then were subjected to prooxidant (DTT) and electrophile (GAPDH) content assays.

Heating caused a linear decay of both activities but with different temperature dependent changes. Both prooxidant and elecrophile activities declined with increased temperatures and at 100^o C, 33% of organic prooxidants and 27% of the electrophiles remained, indicating that ~ 70-75% of the reactive chemicals were destroyed or lost to the atmosphereat 100^o C. At temperatures between 75 and 100^o C, the loss of prooxidants and electrophiles was linear. We were unable to trap the effluent from the heated mixtures for direct chemical balance experiments.

These data show that organic compounds adsorbed on DEPs are not volatile at ambient temperatures but remain adsorbed onto the particle core. They can, however, be extracted by organic solvents or water. A substantial fraction is water soluble as aqueous suspensions of PM exhibit the major prooxidant and some electrophile activity. In a study of 7 DEPs from the EPA, 90% of the DTT activity, 100% of the DHBA activity were in the particles whereas only 24% of the GAPDH activity remained with the particles in an aqueous suspension (Shinyashiki, et al., 2009). These observations are consistent with a particle core or surface of non-polar material to which organic compounds such as PAHs and quinones are adsorbed. The ability of the surface to exhibit prooxidant activity to complex metals isconsistent with proposals of humic like substances associated with particles (Ghio and Quigley, 1994; Ghio, et al., 1996). When presented to a solvent, the adsorbed compounds will partition between the non-polar particle surface and the solvent. Organic solvents will readily remove the organic species and aqueous systems will allow partition between the particle and solvent, resulting in the selective dissolution of polar organics such as quinones.

Distribution of reactive organic chemicals in ambient air samples

The chemical content of particles collected in the Caldecott Tunnel was examined as part of a general study of ambient particles (Ntziachristos, et al., 2007). The results showed metals were highest in the coarse fraction (2.5 – 10 µm) and lowest in the ultrafine (<0.15 µm) fraction, whereas the distribution of organic carbon was the reverse, with the highest percentage (47-74%) in the ultrafine fraction. As these samples were collected in a tunnel, they were minimally affected by photochemical processes.

A study of the distribution of prooxidants and electrophiles in the Basin was conducted with investigators of Project 5. In the first study, large scale samples of particles (PM_2.5) and vapors (XAD resin traps) were collected in Riverside CA (Eiguren-Fernandez, et al., 2010). Consistent with earlier observations, prooxidants were mostly associated with the particle phase in aqueous suspensions and the electrophiles were mostly found in the vapor phase. Subsequently, collections were made at a site next to the 110 freeway at USC and next to the405 freeway near the UCLA campus. Although the collections differed in the time intervals, a comparison was made of the collections at Riverside and the 110 in the summer and the 405 in the spring. The overall activities reflecting prooxidant and electrophile content exhibited minimal differences between the sites. Between 72 to 89% of the prooxidants were found in the aqueous suspension of PM_2.5, whereas 85-98% of the electrophiles were found in the vapor phase. The particle bound prooxidants were found to be mostly metals, as between 76 to 84% of the activity was inhibited by the metal chelator, DTPA.

These distributional studies indicate that reactive chemicals such as quinones, which can exhibit prooxidant and electrophilic chemical reactions, can be removed from diesel exhaust by heating to temperatures > 100^o C and allowing their adsorbtion onto a non-polar media such as carbon. These compounds and redox active metals can be leached from their complex with particles by suspension in aqueous systems and the organic species extracted with appropriate solvents. Studies of ambient air indicate most of the atmospheric electrophiles (> 85%) are present in the vapor phase, which also contains about 25% of the prooxidants. Metals appear to constitute most (>70%) of the particle proxidant activity, so the properties of the ambient air samples at the sites examined (Riverside, USC and Westwood) differ from the DEP samples examined.

Toxicokinetic implications

Cellular access by metal ions is regulated by multiple transporters and redox enzymes, whereas organic compounds, by their non-polar nature tend to enter cells by passive diffusion. However, if the metals are bound in a complex with particles that can enter the cell by phagocytic processes, significant intracellular levels could be achieved. Bound organic species, particularly the prooxidants, also can enter as part of the particle complex, and could allow high intercellular concentrations not achieved by passive diffusion from the external milieu. The electrophiles in the samples are for the most part volatile and likely enter cells by passive diffusion. They would be diluted by the lung lining fluid and enter cells by passive diffusion. Although the intracellular concentration may be low, their actions on tissue nucleophiles are irreversible and recovery can be protracted and cumulative because of its dependency on protein turnover.

Biological effects of air pollutant mixtures

In addition to their actions as proinflammatory agents, studies by Project 2 investigators (Li, et al., 2009) and others have demonstrated the ability of particles to act as adjuvants in the development of the immune response to ovalbumin. These actions appear to involve both organic extractable species as well as the particles themselves and therefore may include metals and reactive organic species (Yanagisawa, et al., 2006). In studies with cell systems, particles and their extracts have been shown to stimulate the expression of proinflammatory cytokines as well as protective pathway proteins such as glutathione transferases and hemeoxygenase-1. The expression of the protective proteins is triggered through activation of the antioxidant response element (ARE) in the DNA for the specific protein by the transcription factor Nrf2 (Rubio, et al.; Dinkova-Kostova, et al., 2002; Itoh, et al., 2004).

To identify potential targets for organic prooxidants and electrophiles, the actions of 1,2-NQ on thiol proteins and macrophage preparations were determined. The quinone inactivated thiol proteins GAPDH and protein tyrosine phosphatase1B, irreversibly by formation of covalent bonds (Kikuno, et al., 2006; Iwamoto, et al., 2007a). In addition, kinases of the MAP kinase pathway were activated, presumably through the activation of the epidermal growth factor receptor (EGFR) (Iwamoto, et al., 2007a). This pathway leads to cell proliferation and the expression of cytokines so it may be one of the proinflammatoryresponses associated with exposure. Simultaneously, the protective pathway initiated by the transcription factor, Nrf2 is activated through covalent bond formation with keap1, the regulatory protein for Nrf2. This transcription factor stimulates the expression of the key protective proteins described earlier. Becasue ambient vapors contain this and other quinones, analogous actions would be expected and these proteins would be likely targets. Subsequent studies with electrophilies in the vapor phase of ambient air samples, indicate that analogous actions occur, including the activation of the EGFR and Nrf2 at concentrations equivalent to exposure to 2-3 m³ of ambient air (Iwamoto, et al., 2010). Thus, electrophilic componentsof vapors form covalent bonds with tissue nucleophiles such as those found on cysteine andlysine residues in proteins, and initiate the same cellular effects found with the prototypical quinone, 1,2-NQ.

5. Summary

The reactive chemical species proposed to affect cellular processes have been found in both particles and vapors of diesel exhaust and ambient air. Samples collected from diesel vehicles operating in a dynamometer system contained mostly organic prooxidants that can be removed by heating to temperatures of 100 to 250^o C. Ambient air particle samples contain most of the prooxidants but as they also contain redox active metals, the prooxidantactivity reflects both metal and organic chemical prooxidants. As the vapor collectionsutilized XAD resin traps that then were extracted with organic solvents, they contain volatile organic species and material balance analyses indicated that ambient air electrophiles were mostly volatile. Thus, exposure to ambient air involves metals and organic prooxidants that can deposit at sites in the lungs, with direct interaction between theparticle and the cell. The particle can serve as a “carrier” allowing the penetration of the cell of metals and organic compounds by phagocytotic processes. Once inside the cell, the adsorbed chemicals could dissociate into the cell milieu and initiate prooxidant actions. The reactive organic vapor phase components, mostly electrophiles, could enter cells by passive diffusion and form covalent bonds with nucleophilic centers in proteins, initiating a different set of cellular responses. Cellular responses to 1,2-NQ have led to the identification of two key proteins, PTP 1B and Keap 1, regulatory proteins for the EGFR and ARE, respectivelyas targets. Activation of these targets lead to cell proliferation and inflammation on the one hand, and protective proteins on the other. The net effect of exposure to both particles and vapors will reflect the combination of prooxidant, both metal and organic, and electrophilic actions.

Future Activities:

The chemical composition of ambient air and diesel exhaust samples in terms of prooxidants and electrophiles has allowed quantitative comparisons between collections at different sites and under different conditions. Samples from common sites with similar chemical composition will be used to address cellular effects. Because particles contain most of the prooxidants and vapors the electrophiles, their relative contributions to a given cellular response can be determined by use of pooled samples of particles and vapors separately and together. These fractions and their combinations will be used to assess the contributions of the two phases to proinflammatory and protective responses in cellular systems. They also will be used to determine the role of prooxidants and electrophiles in the activation of the immune response both in vitro and in vivo.

References:

Kikuno S, Taguchi K, Iwamoto N, Yamano S, Cho AK, Froines JR and Kumagai Y (2006) 1,2- Naphthoquinone activates vanilloid receptor 1 through increased protein tyrosine phosphorylation, leading to contraction of guinea pig trachea. Toxicol Appl Pharmacol 210:47-54.

Li N, Sioutas C, Cho A, Schmitz D, Misra C, Sempf J, Wang M, Oberley T, Froines J and Nel A (2003) Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage. Environ Health Perspect 111:455-460.

Li N, Wang M, Bramble L, Schmitz D, Schauer J, Sioutas C, Harkema J and Nel A (2009) The Adjuvant Effect of Ambient Particulate Matter Is Closely Reflected by the Particulate Oxidant Potential Environ Health Perspect in press.

Ntziachristos L, Froines JR, Cho AK and Sioutas C (2007) Relationship between redox activity and chemical speciation of size-fractionated particulate matter. Part Fibre Toxicol 4:5.

Rodriguez C, Shinyashiki MJ, Froines J, Yu R, Fukuto J and Cho A (2004) An Examination of Quinone Toxicity using the Yeast Saccharomyces cerevisiae Model System. Toxicology 201:185-196. 

Rubio V, Valverde M and Rojas E Effects of atmospheric pollutants on the Nrf2 survival pathway. Environ Sci Pollut Res Int 17:369-382.

Shinyashiki M, Eiguren-Fernandez A, Schmitz DA, Di Stefano E, Li N, Linak WP, Cho SH, Froines JR and Cho AK (2009) Electrophilic and redox properties of diesel exhaust particles. Environ Res 109:239-244.

Taguchi K, Shimada M, Fujii S, Sumi D, Pan X, Yamano S, Nishiyama T, Hiratsuka A, Yamamoto M, Cho AK, Froines JR and Kumagai Y (2008) Redox cycling of 9,10-phenanthraquinone to cause  oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells. Free Radic Biol Med 44:1645-1655.

Yanagisawa R, Takano H, Inoue KI, Ichinose T, Sadakane K, Yoshino S, Yamaki K, Yoshikawa T and Hayakawa K (2006) Components of diesel exhaust particles differentially affect Th1/Th2 response in a murine model of allergic airway inflammation. Clin Exp Allergy 36:386-395.

Journal Articles on this Report : 19 Displayed | Download in RIS Format

Publications Views

Other subproject views:	All 47 publications	27 publications in selected types	All 27 journal articles
Other center views:	All 241 publications	157 publications in selected types	All 157 journal articles

Publications

Type	Citation	Sub Project	Document Sources
Journal Article	Biswas S, Verma V, Schauer JJ, Cassee FR, Cho AK, Sioutas C. Oxidative potential of semi-volatile and non volatile particulate matter (PM) from heavy-duty vehicles retrofitted with emission control technologies. Environmental Science & Technology 2009;43(10):3905-3912.	R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C003 (2009) R832413C003 (2010) R832413C003 (Final)	Abstract from PubMed Full-text: ACS-Full Text HTML Exit Abstract: ACS-Abstract Exit Other: ACS-Full Text PDF Exit
Journal Article	Cho AK, Sioutas C, Miguel AH, Kumagai Y, Schmitz DA, Singh M, Eiguren-Fernandez A, Froines JR. Redox activity of airborne particulate matter at different sites in the Los Angeles Basin. Environmental Research 2005;99(1):40-47.	R832413C003 (2010) R832413C003 (Final) R827352 (Final) R827352C001 (Final) R827352C013 (Final) R827352C014 (Final)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	DiStefano E, Eiguren-Fernandez A, Delfino RJ, Sioutas C, Froines JR, Cho AK. Determination of metal-based hydroxyl radical generating capacity of ambient and diesel exhaust particles. Inhalation Toxicology 2009;21(9):731-738.	R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C003 (2009) R832413C003 (2010) R832413C004 (2010)	Abstract from PubMed Abstract: Taylor and Francis-Abstract Exit
Journal Article	Eiguren-Fernandez A, Miguel AH, Lu R, Purvis K, Grant B, Mayo P, Di Stefano E, Cho AK, Froines J. Atmospheric formation of 9,10-phenanthraquinone in the Los Angeles air basin. Atmospheric Environment 2008;42(10):2312-2319.	R832413 (2007) R832413 (2008) R832413 (Final) R832413C003 (2007) R832413C003 (2008) R832413C003 (2009) R832413C003 (2010) R832413C003 (Final) R827352 (Final)	Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Eiguren-Fernandez A, Miguel AH, Di Stefano E, Schmitz DA, Cho AK, Thurairatnam S, Avol EL, Froines JR. Atmospheric distribution of gas-and particle-phase quinones in Southern California. Aerosol Science and Technology 2008;42(10):854-861.	R832413 (2008) R832413 (Final) R832413C003 (2009) R832413C003 (2010) R832413C003 (Final) R827352 (Final)	Full-text: Taylor&Francis-Full Text HTML Exit Abstract: Taylor&Francis-Abstract Exit Other: Taylor&Francis-Full Text PDF Exit
Journal Article	Eiguren-Fernandez A, Shinyashiki M, Schmitz DA, DiStefano E, Hinds W, Kumagai Y, Cho AK, Froines JR. Redox and electrophilic properties of vapor-and particle-phase components of ambient aerosols. Environmental Research 2010;110(3):207-212.	R832413 (Final) R832413C003 (2010) R832413C003 (Final) R832413C005 (2010) R832413C005 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Hiyoshi K, Takano H, Inoue K, Ichinose T, Yanagisawa R, Tomura S, Cho AK, Froines JR, Kumagai Y. Effects of a single intratracheal administration of phenanthraquinone on murine lung. Journal of Applied Toxicology 2005;25(1):47-51.	R832413C003 (2010) R827352 (2004) R827352 (Final) R827352C001 (Final)	Abstract from PubMed Abstract: Wiley-Abstract Exit
Journal Article	Hu S, Polidori A, Arhami M, Shafer MM, Schauer JJ, Cho A, Sioutas C. Redox activity and chemical speciation of size fractioned PM in the communities of the Los Angeles-Long Beach harbor. Atmospheric Chemistry and Physics 2008;8(21):6439-6451.	R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2009) R832413C001 (Final) R832413C003 (2010) R832413C003 (Final)	Full-text: ACP-Full Text PDF Exit Abstract: ACP-Abstract Exit
Journal Article	Inoue K-I, Takano H, Ichinose T, Tomura S, Yanagisawa R, Sakurai M, Sumi D, Cho AK, Hiyoshi K, Kumagai Y. Effects of naphthoquinone on airway responsiveness in the presence or absence of antigen in mice. Archives of Toxicology 2007;81(8):575-581.	R832413 (2007) R832413 (2008) R832413 (Final) R832413C003 (2007) R832413C003 (2008) R832413C003 (2010)	Abstract from PubMed Abstract: Springer-Abstract Exit
Journal Article	Iwamoto N, Sumi D, Ishii T, Uchida K, Cho AK, Froines JR, Kumagai Y. Chemical knockdown of protein-tyrosine phosphatase 1B by 1,2-naphthoquinone through covalent modification causes persistent transactivation of epidermal growth factor receptor. Journal of Biological Chemistry 2007;282(46):33396-33404.	R832413 (2008) R832413 (Final) R832413C003 (2007) R832413C003 (2008) R832413C003 (2010) R832413C003 (Final)	Abstract from PubMed Full-text: JBC-Full Text HTML Exit Abstract: JBC-Abstract Exit Other: JBC-Full Text PDF Exit
Journal Article	Iwamoto N, Nishiyama A, Eiguren-Fernandez A, Hinds W, Kumagai Y, Froines JR, Cho AK, Shinyashiki M. Biochemical and cellular effects of electrophiles present in ambient air samples. Atmospheric Environment 2010;44(12):1483-1489.	R832413 (Final) R832413C003 (2010) R832413C003 (Final) R832413C005 (2010) R832413C005 (Final)	Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Kikuno S, Taguchi K, Iwamoto N, Yamano S, Cho AK, Froines JR, Kumagai Y. 1,2-Naphthoquinone activates vanilloid receptor 1 through increased protein tyrosine phosphorylation, leading to contraction of guinea pig trachea. Toxicology and Applied Pharmacology 2006;210(1-2):47-54.	R832413C003 (2010) R827352 (Final) R827352C001 (Final)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Kleinman MT, Hamade A, Meacher D, Oldham M, Sioutas C, Chakrabarti B, Stram D, Froines JR, Cho AK. Inhalation of concentrated ambient particulate matter near a heavily trafficked road stimulates antigen-induced airway responses in mice. Journal of the Air & Waste Management Association 2005;55(9):1277-1288.	R832413C003 (2010) R827352 (2004) R827352 (Final) R827352C001 (Final) R827352C005 (Final) R827352C014 (Final)	Abstract from PubMed Full-text: Taylor & Francis-Full Text PDF Exit Abstract: Taylor & Francis-Abstract Exit
Journal Article	Ntziachristos L, Froines JR, Cho AK, Sioutas C. Relationship between redox activity and chemical speciation of size-fractionated particulate matter. Particle and Fibre Toxicology 2007;4:5 (12 pp.).	R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2007) R832413C001 (2008) R832413C001 (Final) R832413C003 (2008) R832413C003 (2010)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: P&FT-Full Text HTML Exit Abstract: P&FT-Abstract Exit Other: P&FT-Full Text PDF Exit
Journal Article	Rodriguez CE, Fukuto JM, Taguchi K, Froines J, Cho AK. The interactions of 9,10-phenanthrenequinone with glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a potential site for toxic actions. Chemico-Biological Interactions 2005;155(1-2):97-110.	R832413C003 (2010) R827352 (Final) R827352C001 (Final)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Shinyashiki M, Rodriguez CE, Di Stefano EW, Sioutas C, Delfino RJ, Kumagai Y, Froines JR, Cho AK. On the interaction between glyceraldehyde-3-phosphate dehydrogenase and airborne particles:evidence for electrophilic species. Atmospheric Environment 2008;42(3):517-529.	R832413 (2008) R832413 (2009) R832413 (Final) R832413C001 (2008) R832413C001 (Final) R832413C003 (2007) R832413C003 (2008) R832413C003 (2010) R832413C003 (Final) R832413C004 (2009) R832413C004 (2010)	Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Shinyashiki M, Eiguren-Fernandez A, Schmitz DA, Di Stefano E, Li N, Linak WP, Cho S-H, Froines JR, Cho AK. Electrophilic and redox properties of diesel exhaust particles. Environmental Research 2009;109(3):239-244.	R832413 (2008) R832413 (Final) R832413C003 (2009) R832413C003 (2010) R832413C003 (Final) R832413C004 (2010)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit
Journal Article	Taguchi K, Fujii S, Yamano S, Cho AK, Kamisuki S, Nakai Y, Sugawara F, Froines JR, Kumagai Y. An approach to evaluate two-electron reduction of 9,10-phenanthraquinone and redox activity of the hydroquinone associated with oxidative stress. Free Radical Biology and Medicine 2007;43(5):789-799.	R832413C003 (2010) R827352 (Final)	Abstract from PubMed Full-text: Science Direct-Full Text HTML Exit Abstract: Science Direct-Abstract Exit Other: Science Direct-Full Text PDF Exit
Journal Article	Taguchi K, Shimada M, Fujii S, Sumi D, Pan X, Yamano S, Nishiyama T, Hiratsuka A, Yamamoto M, Cho AK, Froines JR, Kumagai Y. Redox cycling of 9,10-phenanthraquinone to cause oxidative stress is terminated through its monoglucuronide conjugation in human pulmonary epithelial A549 cells. Free Radical Biology and Medicine 2008;44(8):1645-1655.	R832413 (2007) R832413 (2008) R832413C003 (2007) R832413C003 (2008) R832413C003 (2009) R832413C003 (2010) R827352 (Final)	Abstract from PubMed Full-text: ScienceDirect-Full Text HTML Exit Abstract: ScienceDirect-Abstract Exit Other: ScienceDirect-Full Text PDF Exit

Supplemental Keywords:

Antioxidant response element dihydroxybenzoate dithiothreitol, epidermal growth factor receptor glyceraldehyde-3-phosphate dehydrogenase Nrf2, particles, polycyclic aromatic hydrocarbons, PAHs, quinones, reactive oxygen species, vapors, RFA, Health, Scientific Discipline, Air, particulate matter, Health Risk Assessment, Risk Assessments, Biochemistry, Ecology and Ecosystems, particulates, atmospheric particulate matter, chemical assys, particle matrix, chemical characteristics, human health effects, PM 2.5, toxicology, airway disease, cardiovascular vulnerability, airborne particulate matter, air pollution, human exposure, vascular dysfunction, cardiovascular disease, human health risk

Progress and Final Reports:

Original Abstract

2006 Progress Report

2007 Progress Report

2008 Progress Report

2009 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