Grantee Research Project Results
2003 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, 2003 through January 30, 2004
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 research project 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 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, interstrain differences in dose, as measured by 18O in the lung, will be assessed in neonates.
Considerable progress has been made toward the completion of Aim I. The exposure of 8 inbred strains of neonatal mice to ozone has been completed. Although we targeted the exposure to ozone to occur on day 18 after birth, the unpredictable nature of the timing of conception and the difficulty in conducting research on weekends forced us to examine mice at 16 to 18 days of age. In these initial experiments, we observed considerable intrastrain variability in the response of neonatal mice to a 6-hour exposure to 0.8 ppm ozone. Therefore, based on Dr. Gunnison's earlier time-course work with rats and rabbits exposed to ozone, we briefly examined the response of mice at 12 to 18 days of age. This time-course study showed that the greatest response occurred at approximately 15 days of age. Therefore, all further studies included mice exposed to ozone at 15 or 16 days of age.
Clear interstrain 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 polymorphonuclear neutrophils (PMNs) in lavage fluid. As shown in Figures 1 and 2, SJL, C3H/HeJ, and BALB/C mice were the most sensitive strains and AKR and 129 mice were the most resistant. This interstrain difference in response to ozone suggests that there is a genetic component to the adverse pulmonary effects. Alternatively, as planned in the original grant application, it is possible that these interstrain differences are a result of the strain differences in the dose of ozone that reaches the surface fluid and epithelial cells that line the lung. Therefore, we have ordered adult and neonatal mice from two sensitive and two resistant strains to examine the absorption of ozone generated from 18O. These studies will be done in collaboration with Dr. G. Hatch (U.S. Environmental Protection Agency).
Figure 1. The Effect of 0.8 ppm Ozone on PMNs in the Lavage Fluid of 15/16 Day Old Mice
Figure 2. The Effect of 0.8 ppm Ozone on Total Protein in the Lavage Fluid of 15/16 Day Old Mice
In addition to the interstrain differences in the response of neonatal mice to ozone, we observed a significant effect of gender on the response to ozone in adult mice. A significantly greater response to ozone was observed in female compared to male mice for both percent PMNs (see Figure 3) and protein (see Figure 4). Although these gender differences suggest that genetic factors may play a role in the increased sensitivity of female mice, the magnitude of the interstrain differences suggests that this may be a minor contribution. We also observed a general increase in the protein phenotype in lactating mice compared to age-matched female mice, whereas the PMN phenotype differences were biologically significant only in the A/J strain.
Figure 3. The Effect of 0.8 ppm Ozone on PMNs in the Lavage Fluid of Adult Mice
Figure 4. The Effect of 0.8 ppm Ozone on Total Protein in the Lavage Fluid of Adult Mice
Future Activities:
As hypothesized, ozone appears to produce more adverse effects in neonatal mice than in adult male or female mice. We will focus our future work on the genetic factors that control this increased susceptibility. These studies will include microarray and linkage analysis experiments.
Journal Articles:
No journal articles submitted with this report: View all 2 publications for this projectSupplemental Keywords:
ozone, ambient air, mice, genetic factors, genetic susceptibility, child, inhalation, neonatal lung, pulmonary exposure, age-related differential response, international cooperation, age-related differences, biological response, children?s environmental health, children's vulnerability, exposure assessment, gene-environment interaction, genetic mechanisms, genetic predisposition, genetic risk factors, ozone-induced airway dysfunction., 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.