Grantee Research Project Results

2007 Progress Report: Mechanistic Research Project

EPA Grant Number: R832141C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R832141
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Columbia Center for Children’s Environmental Health
Center Director: Perera, Frederica P.
Title: Mechanistic Research Project
Investigators: Rothman, Paul B. , Chen, Lung Chi , Miller, Rachel L. , Grunig, Gabriele
Institution: Columbia University in the City of New York , New York University
EPA Project Officer: Callan, Richard
Project Period: November 1, 2003 through October 31, 2008 (Extended to October 31, 2010)
Project Period Covered by this Report: November 1, 2006 through October 31, 2007
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text |  Recipients Lists
Research Category: Children's Health , Human Health

Objective:

Specific aims are to use mouse models to determine whether: 1) in utero sensitization increases the risk for subsequent airway hyperreactivity and antigen-induced inflammation; 2) diesel exhaust particles, endemic to the Northern Manhattan environment, promote antigen-specific prenatal sensitization, and whether this occurs by upregulating Th2-mediated allergic responses, and whether PAHs, measured by PAH-adducts in lung tissue, mediates this response; and 3) endotoxin protects from the development of antigen-specific prenatal sensitization, and whether this occurs by upregulating Th1-mediated immune processes.

Progress Summary:

Inhaled exposure to the mold aspergillus fumigatus (A. fumigatus) may inhibit IgE production across 2-3 generations.

In early studies, exposure of female mice to A. fumigatus led to a twofold reduction in IgE production in the offspring (p=0.029). The effect appears to more pronounced when examining the effects on the third generation offspring. Grandparental exposure to A. fumigatus both at high (1.25 mg) (Figure 1) and medium (62.5 micrograms) doses resulted in repeatable reductions in IgE levels in the third generation mice. Effects on airway hyprreactivity are less consistent. The effects of prenatal exposure to diesel exhaust particles are less consistent.

Figure 1: Grandparental exposure to mold protects against the development of IgE

Effects of prenatal diesel exhaust particle (DEP) exposure in combination with mold Aspergillus fumigatus (Asp Ag) on asthma-like outcomes in mice

To date prenatal exposure of female mice to A. fumigatus at 62.5 micrograms in combination with prenatal exposure to daily diesel induces variable immune responses in the offspring. Experiments are being repeated to determine true effects in our model system.

Combined inhaled diesel exhaust particles and allergen exposure alter methylation of T helper genes and IgE production in vivo

In additional experiments, we hypothesized that diesel exhaust particles (DEP) would induce hypermethylation of the IFNg promoter and hypomethylation of IL-4 in CD4+ T cells among mice sensitized to A. fumigatus.We also hypothesized that DEP-induced methylation changes would affect immunoglobulin (Ig) E regulation. Balb/c mice were exposed to a 3 week course of inhaled DEP exposure while undergoing intranasal sensitization to A. fumigatus. Purified DNA from splenic CD4+ cells underwent bisulfite treatment, PCR amplification and pyrosequencing. Sera IgE levels were compared to methylation levels at several CpG sites in the IL-4 and IFNg promoter. Total IgE production was increased following intranasal sensitization A. fumigatus. IgE production was augmented further following combined exposure to A. fumigatus and DEP exposure. Inhaled DEP exposure and intranasal A. fumigatus induced hypermethylation at CpG^-45, CpG^-53, CpG^-205 sites of the IFNg promoter and hypomethylation at CpG^-408 of the IL-4 promoter. Altered methylation of promoters of both genes was correlated with changes in IgE levels.

Significance

Our study is the first to demonstrate that inhaled exposures influence methylation of Th genes in vivo, supporting a new paradigm in asthma pathogenesis.

Future Activities:

Our priorities are twofold and include: 1) To repeat experiments on the multigenerational effects of exposure to A. fumigatus 2) To repeat experiments on the multigenerational effects of prenatal diesel exhaust particle exposure.

Supplemental Keywords:

Health, RFA, Scientific Discipline, Air, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Environmental Policy, Children's Health, Biochemistry, air toxics, Genetics, Risk Assessment, genetic mechanisms, health effects, Human Health Risk Assessment, diesel exhaust, maternal exposure, environmental risks, genetic risk factors, genetic susceptibility, diesel exhaust particulate, nutritional risk factors, assessment of exposure, PAH, children's environmental health

Progress and Final Reports:

Original Abstract

2004 Progress Report

2005 Progress Report

2006 Progress Report

2008

2009

Final

Main Center Abstract and Reports:

R832141    Columbia Center for Children’s Environmental Health

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R832141C001 Growth and Development Research Project: Prenatal and Postnatal Urban Pollutants and Neurobehavioral Developmental Outcomes
R832141C002 Research Project on Asthma: Prenatal and Postnatal Urban Pollutants and Childhood Asthma
R832141C003 Mechanistic Research Project
R832141C004 Community-Based Intervention Project: Reduction of Exposure and Risk from Pesticides and Allergens
R832141C005 Community Translation and Application Core (COTAC)
R832141C006 Exposure Assessment Facility Core
R832141C007 Data Management, Statistics and Community Impact Modeling Core
R832141C008 Administrative Core