Grantee Research Project Results
2004 Progress Report: Genetic Basis of the Increased Susceptibility of Children to Inhaled Pollutants
EPA Grant Number: R830755Title: Genetic Basis of the Increased Susceptibility of Children to Inhaled Pollutants
Investigators: Gordon, Terry , Chen, Lung Chi , Gunnison, Albert F. , Tang, Eric
Current Investigators: Gordon, Terry , Chen, Lung Chi , Gunnison, Albert F.
Institution: New York University School of Medicine
EPA Project Officer: Aja, Hayley
Project Period: January 31, 2003 through January 30, 2006 (Extended to January 30, 2007)
Project Period Covered by this Report: January 31, 2004 through January 30, 2005
Project Amount: $749,175
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The objective of this study is to determine the biological mechanism underlying the increased susceptibility of children to inhaled pollutants. We hypothesize that 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 versus 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.
Progress Summary:
Aim I
To test the hypothesis that there is a genetic basis for the difference in response of neonate 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, inter-strain differences in dose, as measured by 18O in the lung, will be assessed in neonates.
Aim I has been completed. Eight inbred strains of neonatal mice have been exposed to ozone. Although we initially targeted the exposure to ozone to occur on day 18 after birth, a time-course study showed that the greatest response occurred at approximately 15 days of age and, therefore, all neonatal studies included mice exposed to ozone at 15 or 16 days of age.
Clear inter-strain differences in response to ozone were observed in neonatal mice exposed to ozone at 15 or 16 days after birth. These changes were observed for the phenotypes used to study lung injury (protein) and inflammation (PMNs) in lavage fluid. As reported last year, SJL, C3H/HeJ, and BALB/C mice were the most sensitive strains, and AKR, A/J, and 129 mice were the most resistant.
This inter-strain difference in response to ozone suggested that there is a genetic component to the adverse pulmonary effects. Alternatively, as planned in the original grant application, it is possible that these inter-strain differences were the result of strain differences in the dose of ozone that reaches the surface fluid and epithelial cells that line the lung. Therefore, adult and neonatal mice from two sensitive and two resistant strains were exposed to ozone generated from 18O to examine the dose of ozone delivered to each strain. These studies were done in collaboration with Dr. G. Hatch (U.S. Environmental Protection Agency) and demonstrated that the dose of ozone delivered to the lung was not important in the observed inter-strain differences in lung injury and inflammation in neonatal mice. Moreover, the ozone dose did not account for the increased susceptibility of neonatal mice compared to adult mice.
Aim 2
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 classic genetic 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 cross-linked to microarray expression data.
The experiments proposed in Aim 2 are nearly complete. An F2 generation of neonatal mice was bred from F1 mice generated from sensitive BALB/C and resistant A/J progenitor mice and then exposed to ozone using the protocol identical to that used to expose the eight strains of inbred neonatal and adult mice. The response of F1 neonatal mice suggested that the sensitivity/resistance of the mice to ozone-induced lung injury and inflammation was a heritable trait. The F2 mice have been phenotyped, their DNA isolated, and the genotyping is almost complete.
The second proposed experiment, to develop microarray expression data to compare to the significant loci identified by the quantitative linkage analysis study in the F2 mice, has been completed and the expression array data are now in the analysis stage.
Future Activities:
As hypothesized, ozone appears to produce more adverse effects in neonatal mice than in adult male or female mice. We will therefore focus our work on the genetic factors that control this increased susceptibility. These analyses will include the integration of data from the microarray and linkage analysis experiments.
Journal Articles:
No journal articles submitted with this report: View all 2 publications for this projectSupplemental Keywords:
ozone, children, ambient air, mice, genetic susceptibility, exposure assessment,, 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 assessmentProgress and Final Reports:
Original AbstractThe 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.