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2005 Progress Report: Mechanistic Research Project
EPA Grant Number: R832141C003Subproject: 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 , Grunig, Gabriele , Miller, Rachel L.
Current Investigators: Rothman, Paul B.
Institution: Columbia University
EPA Project Officer: Fields, Nigel
Project Period: November 1, 2003 through October 31, 2008
Project Period Covered by this Report: November 1, 2004 through October 31, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003)
Research Category: Children's Health , Health Effects
Description:
Objective:The objectives of this research project 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, if this occurs by upregulating Th2-mediated allergic responses, and if PAHs, measured by PAH-adducts in lung tissue, mediate 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:Development of Mouse Model for in utero Sensitization to Ovalbumin
Our data, concordant with recently published results from a murine asthma model, support the hypothesis that sensitization in utero to ovalbumin (OVA) occurs. We found that offspring of mice sensitized and challenged with OVA exhibited increased airway hyperresponsiveness, increased allergic pulmonary inflammation, increased T cell proliferation, and increased levels of OVA-specific IgE compared to offspring of nontreated mice, similar to published reports. These data, in support of Objective 1, suggest that a pregnant mouse sensitized to OVA, and probably in the presence of a Th2-polarized state, can transfer an asthma-like phenotype to her offspring.
Development of Mouse Model for in utero Sensitization to Aspergillus
Female mice were exposed to the aerosolized mold Aspergillus prior to mating, and their offspring were examined for increased Aspergillus-induced airway hyperreactivity and airway inflammation. Preliminary data suggest that offspring born to mothers exposed prenatally to Aspergillus (dose 12.5 or dose 25) developed increased airway hyperreactivity (AHR) and inflammatory cells in their bronchoalveolar fluid compared to naïve mice (Figure 1).
Figure 1. AHR in Mice Exposed to Aspergillus
These results suggest that in utero sensitization to environmental inhaled allergens may occur in our mouse model.
Role of Dendritic Cells in in utero Sensitization
We also asked the more mechanistic question as to whether in utero sensitization may be mediated by dendritic cells. Bone marrow derived dendritic cells (BMDC) were loaded with OVA immune complexes and injected during late pregnancy, and offspring were challenged with suboptimally low doses of OVA at age 4 weeks. Offspring born to mothers exposed to BMDC were found to have higher levels of total and OVA-specific IgE.
Significance
These results corroborate that in utero sensitization to OVA, and possibly the inhaled mold Aspergillus, occurs in reliable mouse models. Fetal dendritic cells are important mediators.
Future Activities:We will: (1) analyze cockroach sensitization protocols (already initiated); (2) repeat and confirm the Aspergillus model and stringently compare immunological outcomes with the OVA model; and (3) determine whether endotoxin protects against the development of antigen-specific prenatal sensitization. We also plan to test our models in several knockout mice (e.g., Stat6) to help determine the mechanism for in utero sensitization to antigens in a manner that would not be feasible in human subjects.
Supplemental Keywords:children’s health, genetics, health effects, health risk assessment, assessment of exposure, endotoxins, PAHs, OVA, environmental risks, environmental exposure, exposure assessment, genetic risk factors, genetic susceptibility, maternal exposure, nutritional risk factors, diesel exhaust,
,
ENVIRONMENTAL MANAGEMENT, INTERNATIONAL COOPERATION, Air, Scientific Discipline, Health, RFA, Risk Assessment, Health Risk Assessment, air toxics, Children's Health, Biochemistry, Environmental Policy, Genetics, exposure assessment, health effects, genetic risk factors, children's environmental health, diesel exhaust, assessment of exposure, genetic susceptibility, maternal exposure, diesel exhaust particulate, nutritional risk factors, genetic mechanisms, environmental risks, PAH
Relevant Websites:
Progress and Final Reports:
2004 Progress Report
Original Abstract
2006 Progress Report
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