Final Report: Children's Exposure to Environmental Tobacco Smoke: Changes in Allergic Response

EPA Grant Number: R826708C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R826708
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Southern California Particle Center and Supersite
Center Director: Froines, John R.
Title: Children's Exposure to Environmental Tobacco Smoke: Changes in Allergic Response
Investigators: Gong, Henry , Diaz-Sanchez, David
Institution: Rancho Los Amigos Medical Center , University of California - Los Angeles
EPA Project Officer: Louie, Nica
Project Period: January 1, 1998 through January 1, 2002
Project Amount: Refer to main center abstract for funding details.
RFA: Centers for Children's Environmental Health and Disease Prevention Research (1998) RFA Text |  Recipients Lists
Research Category: Children's Health , Health Effects , Health

Objective:

Aim #1: To determine whether lung functional growth is decreased and respiratory illnesses are increased by low dietary intake of fruits and vegetables; low dietary intake of antioxidant vitamins; homozygosity for the common (A) allele in promoter region of MPO (polymorphic allele has a G to A at position-463 of the MPO gene); and presence of one TNF2 allele.

Aim #2: To determine whether susceptibility to (1) slow lung functional growth; (2) respiratory symptoms; and (3) respiratory illness from exposure to O3, NO2, PM10, and PM2.5 is increased by low dietary intake of fruits and vegetables; low dietary intake of antioxidant vitamins; high intake of dietary fat with a high polyunsaturated fat to total fat ratio; homozygosity for the null allele at the GSTM1 and GSTT1 loci, or the presence of one A105G allele at the GSTP1 locus; homozygosity for the common (A) allele in the promoter region of MPO; and presence of one TNF2 allele.

Summary/Accomplishments (Outputs/Outcomes):

We have completed each of the primary specific aims and summarize the published results below. Note that we studied ICAM1 instead of MPO based on the importance of ICAM1 in the initial inflammatory response. We genotyped 3885 children for GSTM1, GSTP1, GSTT1, TNF, and ICAM1 (3 single nucleotide polymorphisms [SNPs]: 29, 241, 469). We assessed the main effects of gene-air pollutants and gene-gene interactions on asthma, lung function, and respiratory illnesses. We studied the effects of GSTM1, GSTT1, and GSTP1 on asthma occurrence in a nested-case control study of 2264 children in the Children’s Health Study (CHS). Our primary findings include:

  1. GSTM1 null or GSTP1 A105G variant genotypes were associated with reduced lung function growth (Gilliland, et al., 2002a).
  2. In utero exposure to maternal smoking increased the risk of asthma among children with GSTM1 null or GSTP1 A105G variant genotypes (Gilliland, et al., 2003a; Gilliland, et al., 2002b).
  3. The risk of asthma was highest in children with GSTM1 null and GSTP1 variant genotype (Gilliland, et al., 2003a).
  4. Risk of respiratory-related school absences varied by GSTM1 and GSTP1 genotype (Gilliland, et al., 2002c).
  5. TNF–308 genotype was associated with early life asthma prevalence, but the effect of the genetic variant is limited to low O3 communities (Gilliland, et al., 2003b).
  6. ICAM1 haplotypes were associated with early onset persistent asthma (Li, et al., 2004).
  7. Diets low in antioxidant vitamins were associated with deficits in lung function (Gilliland, et al., 2001; Gilliland, et al., 2002d).
  8. Low magnesium intake was associated with lung function deficits (Gilliland, et al., 2002d).

Polymorphisms of GSTP1 are associated with early onset asthma (before age 5 years) and severity of wheezing. We conducted analyses of the risk for newly diagnosed asthma among CHS participants and found a significant protective effect for the GSTP1 valine (val) allele that was largest in children who participated in team sports (data not shown). We hypothesized that the effects of in utero exposure on asthma would be largest among children with GSTM1 null genotype. We found a significant interaction of the null genotype of GSTM1 and in utero exposure to maternal smoking on asthma prevalence and wheezing. In a preliminary study, we also found a significant interaction of the null genotype of GSTM3 and in utero exposure to maternal smoking on early onset asthma (data not shown). We observed an interaction between GSTP1 and GSTM1 in the occurrence of persistent asthma. Children with the GSTM1 null and homozygous GSTP1 val 105 allele had a 2.4-fold increase in early onset asthma and a 50 percent increase in the risk of persistent asthma compared to those who were homozygous for the wild type alleles. We observed a statistically significant interaction between GSTM1 and GSTP1 and asthma, including lifetime risk of asthma, persistent asthma, and use of medications for asthma.

We observed a statistically significant interaction between GSTM1 and air pollutants on lung function growth, especially measures of small airway flows. In analyses of cohort D (an additional cohort of 2000 4th grade students enrolled 3 years after the CHS was initiated), deficits in maximum mid-expiratory flow (MMEF) and forced expiratory volume during first second of expiration (FEV1 ) were associated with exposure to PM10, PM2.5, NO2, and vapor acids, but only among children who were GSTM1 null. We examined the effects of GSTM1, P1, and T1 on respiratory illness-related school absenteeism. In analyses of school absenteeism in 1996 in 4th graders, we found that GSTP1, but not GSTM1 or T1, was associated with rates of respiratory related absences.

To further examine the role of GSTs in respiratory outcomes, we conducted a randomized crossover trial of the adjuvant effects of diesel exhaust particles (DEP) on nasal responses to allergen challenge in 19 allergic subjects (Gilliland, et al., 2004). Ragweed allergen sensitive subjects were challenged intranasally with allergen alone and with allergen plus DEP in a randomized order at separate visits. Nasal allergen-specific IgE, histamine, IL-4, and interferon-γ (INF-γ) levels were measured before and 24 hours after challenge. Individuals with GSTM1 null or the GSTP1 ile105 wildtype genotypes showed enhanced nasal allergic responses in the presence of DEP. Compared to subjects with a functional GSTM1 genotype, GSTM1 null subjects had a significantly larger increase in IgE (median 102.5 vs. 45.5 U/mL, p = 0.03) and histamine (median 14.0 vs. 7.4 nM, p = 0.02) following DEP plus allergen challenge. The ile105 GSTP1 genotype was associated with an increase in IgE (median 120.3 vs. 27.7 U/mL, p = 0.03) and histamine (median 13.8 vs. 5.2 nM, p = 0.01) following DEP plus allergen challenge. We concluded that GSTM1 and GSTP1 modify the adjuvant effect of DEP on allergic inflammation. These findings have been replicated in two additional trials using fel d1 and secondhand smoke exposure, respectively (manuscripts in preparation). Findings that the adjuvant effects of DEP can be blocked by N-acetyl-cysteine support the critical role of glutathione (Whitekus, et al., 2002). We found no consistent association with GSTT1 null genotype and respiratory health outcomes. We found that dietary fat intake was not strongly associated with lung function or asthma occurrence (data not shown).

References:

Gilliland FD, Gauderman WJ, Vora H, Rappaport E, Dubeau L. Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth. American Journal of Respiratory and Critical Care Medicine 2002a;166(5):710-716.

Gilliland FD, Li Y-F, Tsai W, Dubeau L. GSTP1 and GSTM1 contribute to susceptibility for asthma and wheezing following in utero exposure to tobacco smoke. American Journal of Respiratory and Critical Care Medicine 2003a;167:A942.

Gilliland FD, Li Y-F, Tsai W, Dubeau L, Avol E, Peters JM. TNFα - 308 genotype and ozone effects on asthma and wheezing: results from the Children’s Health Study (CHS). American Journal of Respiratory and Critical Care Medicine 2003b;167:A580.

Li Y-F, Tsao Y-H, Wenten MR, Dubeau L, Gilliland FD. Intercellular adhesion molecule 1 haplotypes and childhood asthma risk. American Journal of Respiratory and Critical Care Medicine 2004;169:A583.

Gilliland F, Li Y, Peters J. Effects of vitamin A, C, and E intake on children’s lung function. American Journal of Respiratory and Critical Care Medicine 2001;163:A37.

Gilliland FD, Rappaport EB, Berhane K, Islam T, Dubeau L, Gauderman WJ, McConnell R. Effects of glutathione S-transferase P1, M1, and T1 on acute respiratory illness in school children. American Journal of Respiratory and Critical Care Medicine 2002;166(3):346-351.

Gilliland FD, Berhane KT, Li Y-F, Kim DH, Margolis HG. Dietary magnesium, potassium, sodium, and children’s lung function. American Journal of Epidemiology 2002d;155(2):125-131.


Journal Articles on this Report : 3 Displayed | Download in RIS Format

Other subproject views: All 4 publications 4 publications in selected types All 4 journal articles
Other center views: All 92 publications 63 publications in selected types All 61 journal articles
Type Citation Sub Project Document Sources
Journal Article Gilliland FD, Gauderman WJ, Vora H, Rappaport E, Dubeau L. Effects of glutathione-S-transferase M1, T1, and P1 on childhood lung function growth. American Journal of Respiratory and Critical Care Medicine 2002;166(5):710-716. R826708 (Final)
R826708C002 (Final)
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  • Journal Article Gilliland FD, Li Y-F, Saxon A, Diaz-Sanchez D. Glutathione-S-Transferase M1 and P1 genotypes protect against xenobiotic enhancement of allergic responses. Lancet 2004;363:119-125. R826708C002 (Final)
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  • Journal Article Whitekus MJ, Li N, Zhang M, Wang M, Horwitz MA, Nelson SK, Horwitz LD, Brechun N, Diaz-Sanchez D, Nel AE. Thiol antioxidants inhibit the adjuvant effects of aerosolized diesel exhaust particles in a murine model for ovalbumin sensitization. Journal of Immunology 2002;168(5):2560-2567. R826708 (2000)
    R826708 (2001)
    R826708 (2002)
    R826708 (Final)
    R826708C001 (Final)
    R826708C002 (Final)
    R827352 (Final)
    R827352C002 (Final)
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  • Supplemental Keywords:

    children’s health, respiratory health, allergic airway disease, secondhand smoke, air pollution, diesel exhaust particles, integrated pest management, community-based participatory research, susceptibility, genetics, gene expression, inflammation,, RFA, Health, Scientific Discipline, Air, Environmental Chemistry, Health Risk Assessment, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Allergens/Asthma, Children's Health, genetic susceptability, indoor air, Atmospheric Sciences, Biology, asthma, health effects, sensitive populations, cytokines, pollen, allergic rhinitis, infants, airway disease, biological response, respiratory problems, second hand smoke, exposure, children, Human Health Risk Assessment, airway inflammation, assessment of exposure, childhood respiratory disease, children's vulnerablity, susceptibility, tobacco, human exposure, cigarette smoke, environmentally caused disease, indoor air quality, allergic response, tobacco smoke, allergen, exposure assessment, indoor environment, copollutant, environmental hazard exposures

    Relevant Websites:

    http://www.usc.edu/schools/medicine/departments/preventive_medicine/divisions/occupational/occ_environmental/cehc/index.html Exit

    Progress and Final Reports:

    Original Abstract
  • 1998
  • 1999
  • 2000 Progress Report

  • Main Center Abstract and Reports:

    R826708    Southern California Particle Center and Supersite

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R826708C001 Asthma in Children: A Community-based Intervention Project
    R826708C002 Children's Exposure to Environmental Tobacco Smoke: Changes in Allergic Response
    R826708C003 Respiratory Disease and Prevention Center