Genetic Basis of the Increased Susceptibility of Children to Inhaled Pollutants

EPA Grant Number: R830755
Title: Genetic Basis of the Increased Susceptibility of Children to Inhaled Pollutants
Investigators: Gordon, Terry
Current Investigators: Gordon, Terry , Chen, Lung Chi , Gunnison, Albert F.
Institution: New York University
EPA Project Officer: Deener, Kacee
Project Period: January 31, 2003 through January 30, 2006 (Extended to January 30, 2007)
Project Amount: $749,175
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Health

Description:

Objective/Hypothesis:

The objective of this study is to determine the biological mechanism underlying the increased susceptibility of children to inhaled pollutants. We hypothesize that there is a genetic basis for the differential response of neonatal and adult rodent lungs to inhaled pollutants. In testing this hypothesis, we will: 1) quantify the contribution of genetic vs. environmental factors; 2) identify candidate genes that play a critical role in the molecular pathways leading to the increased susceptibility of the neonatal lung; and 3) compare these genes to those involved in adult lung toxicity. Our preliminary studies have demonstrated that ozone produces greater inflammation and injury in neonatal lungs. We will expand upon these findings and identify genes responsible for the age-related differential response to inhaled ozone.

Approach:

To test the hypothesis that there is a genetic basis for the difference in response of neonatal and adult mice to inhaled pollutants, 10 inbred strains of neonatal mice will be exposed to ozone and examined for lung injury and inflammation. To insure that strain differences in response are genetic in nature, interstrain differences in dose, as measured by 18O in the lung, will also be assessed in neonates. To identify candidate genes that play a critical role in the differential response of neonatal and adult mice to ozone, we will identify quantitative trait loci (QTLs) that are associated with the response of neonatal mice to ozone by using both a classical genetic cross-breeding method and a state-of-the-art computational genomics method. To identify the most likely candidate genes within these chromosomal loci, the QTL results will be linked to microarray expression data.

Expected Results:

As determined in preliminary studies, inhaled ozone should produce enhanced lung injury in neonatal mice. We also expect that the genetic factors that govern the increased sensitivity of the neonatal lung will be different than those which govern the response of the adult lung. Therefore, we expect to find a different inter-strain pattern of response to ozone in the neonatal mice. This strain data and the proposed genetic analyses will rapidly identify genes which can be tested as candidates for governing the neonatal response. The data obtained in the proposed study can be extrapolated to the human infant by studying homologous genes in the human genome. In summary, the results from this study address a number of the research needs identified in the solicitation, including: examining age-related differences in target organ responses at the molecular level and developing animal models to assist in elucidating age-related susceptibility factors.

Publications and Presentations:

Publications have been submitted on this project: View all 1 publications for this project

Supplemental Keywords:

ozone, child, inhalation, neonatal lung, pulmonary exposure, genetic factors, age related differential response, RFA, Health, Scientific Discipline, INTERNATIONAL COOPERATION, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Children's Health, Environmental Policy, Biology, Risk Assessment, sensitive populations, age-related differences, biological response, gene-environment interaction, genetic predisposition, air pollution, genetic mechanisms, ozone induced airway dysfunction, assessment of exposure, children's vulnerablity, genetic risk factors, inhalation, susceptibility, children's environmental health, exposure assessment

Progress and Final Reports:

2003 Progress Report
2004 Progress Report
2005 Progress Report
Final Report