Grantee Research Project Results

2012 Progress Report: Ambient Pollutant/Bioaerosol Effects on Treg Function

EPA Grant Number: R834596C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834596
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for Integrative Research on Childhood Leukemia and the Environment - 2015
Center Director: Metayer, Catherine
Title: Ambient Pollutant/Bioaerosol Effects on Treg Function
Investigators: Tager, Ira , Hammond, S. Katharine , Balmes, John R. , Eisen, Ellen , Nadeau, Kari
Institution: University of California - Berkeley , University of California - San Francisco , Harvard University , Stanford University
Current Institution: University of California - Berkeley , Stanford University
EPA Project Officer: Callan, Richard
Project Period: May 7, 2010 through May 6, 2013 (Extended to May 6, 2014)
Project Period Covered by this Report: May 7, 2012 through May 6,2013
RFA: Children's Environmental Health and Disease Prevention Research Centers: Formative Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health

Objective:

The overall goal of this research is to further understand the link between indicators of exposure and outcomes on human health by studying immune system changes in subjects exposed to elevated levels of ambient air pollution. We hypothesize that immunological indicators linked to environmental exposure and health outcomes will elucidate the role and mechanism of air pollution in asthma, a link which is theoretically understood, circumstantially clear, but not yet proven. We have developed a comprehensive novel indicator of hazard exposure that can be performed on one drop of blood. We will correlate cellular, serological, and epigenetic biomarker changes in peripheral blood which can be broadly applied to an individual health outcome. The objectives of the research are (1) to examine the link between specific immune indicators and ambient air pollution exposure (level of exposure, chronicity of exposure, and type of exposure: ozone, NO/NO₂, CO, PM_2.5, PM₁₀, sulfate, elemental carbon, polyaromatic hydrocarbons, daily naphthalene, endotoxin, fungal spores, and/or pollens) through a database collected in a large population in Fresno, CA; and (2) to characterize the relationship between immune indicators and health outcomes of asthma.

Progress Summary:

The work on the project aims has proceeded smoothly and at the pace anticipated. All has progressed according to timelines and all subjects have been recruited and are enrolled in the study. We are in the process of performing all cellular and molecular analyses on the blood samples obtained from the subjects. Some preliminary results and publications have occurred and these are detailed below. The aims of the project are unchanged.

As described in the preliminary results section below, significant immunotoxic effects were observed using in vivo and ex vivo studies.

Results expected during the project. Our preliminary data demonstrate:

that DNA methylation of the Foxp3 gene results in decreased FoxP3 protein levels in Treg and that the levels of FoxP3 decrease are associated with increases in levels of exposure to polycyclic aromatic hydrocarbons,
that downregulation of chemokine receptor/cognate ligand pairs (CCR8/CCL1) is worsened by exposure to polycyclic aromatic hydrocarbons,
that decreases in Treg-associated (TGF-β and IL-10) and increases in Th2-associated plasma markers (IL-4 and IL-13) correlate with increased levels of exposure to ambient air pollution,
that higher degrees of Treg impairment correlate with severity of asthma, and
that lower levels of Treg immune indicators can be detected in non-asthmatic children exposed to elevated levels of ambient air pollution and that if the Treg immune indicators increase over the 4 time points of the study (baseline, 6 mo, 12 mo and 18 mo), then these children might be at risk for developing asthma. Definitive analysis for the positive predictive value of a Treg immune indicator is outside the scope of this study but we plan to collect evidence in this proposed research to further test predictive value in the future.

We expect our results to:

provide sufficient evidence to help understand the link between the environmental hazard, exposure (individual estimate exposures), and the health outcomes (asthma) through the database collected in a large population in Fresno, CA
characterize the relationship between ambient air pollution exposure and biomarkers that can be used to indicate the health outcomes of asthma.

Overall Impact: The proposal is aimed to innovatively examine whether chronic ambient air exposures, the health outcomes of individual children, and changes in the immune system are correlated. The results are essential for understanding immune mechanisms that could be related to exposure and health outcomes. Overall, the results would help in decreasing and preventing the burden of asthma and allergy and reducing exposure to air pollution.

Future Activities:

Future activities are to:

Complete all collection of samples and clinical outcome measures every 6 months.
Complete our analysis of repeat immune measures (i.e., Treg function, Foxp3 expression, DNA methylation of Foxp3 locus) and repeat clinical outcomes (pulmonary function tests and health questionnaires) on each subject.
Obtain short-term and long-term individual estimate exposures to ambient air PAHs, PM_2.5, black carbon, and ozone, and then test whether there is an association of the extent of exposure in each subject to immune outcome measures in the same subject.

If data represent interesting findings, we will submit a manuscript on the EPA-funded cohorts.

Journal Articles on this Report : 4 Displayed | Download in RIS Format

Publications Views
Other subproject views:	All 28 publications	6 publications in selected types	All 6 journal articles
Other center views:	All 50 publications	15 publications in selected types	All 15 journal articles

Publications
Type	Citation	Sub Project	Document Sources
Journal Article	Balmes JR. How does diesel exhaust impact asthma? Thorax 2011;66(1):4-6.	R834596 (2010) R834596 (2011) R834596 (2012) R834596 (Final) R834596C003 (2012)	Abstract from PubMed Full-text: BMJ-Full Text HTML Exit Abstract: BMJ-Extract Exit Other: BMJ-Full Text PDF Exit
Journal Article	Gale SL, Noth EM , Mann J, Balmes J, Hammond SK, Tager IB. Polycyclic aromatic hydrocarbon exposure and wheeze in a cohort of children with asthma in Fresno, CA. Journal of Exposure Science & Environmental Epidemiology 2012;22(4):386-392.	R834596 (2010) R834596 (2011) R834596 (2012) R834596 (Final) R834596C003 (2012)	Full-text from PubMed Abstract from PubMed Associated PubMed link Abstract: Nature-Abstract Exit
Journal Article	Kohli A, Garcia MA, Miller RL, Maher C, Humblet O, Hammond SK, Nadeau K. Secondhand smoke in combination with ambient air pollution exposure is associated with increased CpG methylation and decreased expression of IFN-γ in T effector cells and Foxp3 in T regulatory cells in children. Clinical Epigenetics 2012;4(1):17 (16 pp.).	R834596 (2011) R834596 (2012) R834596 (Final) R834596C003 (2011) R834596C003 (2012) R834596C003 (Final) R834786 (2012) R835435 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Full text Abstract: Abstract Other: BioMed Central-Full Text PDF Exit
Journal Article	Liu J, Zhang L, Winterroth LC, Garcia M, Weiman S, Wong JW, Sunwoo JB, Nadeau KC. Epigenetically mediated pathogenic effects of phenanthrene on regulatory T cells. Journal of Toxicology 2013;2013:967029.	R834596 (2012) R834596 (Final) R834596C003 (2012) R834596C003 (Final) R834786 (2012) R835435 (Final)	Full-text from PubMed Abstract from PubMed Associated PubMed link Full-text: Full text Abstract: Abstract Other: Hindawi Publishing-Full Text PDF Exit

Supplemental Keywords:

immune function, Foxp3, immune system, epigenetic effects, RFA, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, HUMAN HEALTH, Epidemiology, Health Effects, Biochemistry, Children's Health, Biology, Risk Assessment, asthma, air toxics, prenatal exposure, biological response, measuring childhood exposure, air pollution, assessment of exposure, childhood respiratory disease, children's vulnerablity, harmful environmental agents, developmental disorders

Relevant Websites:

CHAPS - SJV Exit

Progress and Final Reports:

Original Abstract

2010 Progress Report

2011 Progress Report

Final Report

Main Center Abstract and Reports:

R834596 Center for Integrative Research on Childhood Leukemia and the Environment - 2015

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834596C001 Effect of Multi-Level Environmental Exposure on Birth Outcomes
R834596C002 Exposure to Air Pollutants and Risk of Birth Defects
R834596C003 Ambient Pollutant/Bioaerosol Effects on Treg Function

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.