Grantee Research Project Results
Final Report: Pollution-Enhanced Allergic Inflammation and Phase II Enzymes
EPA Grant Number: R831861C002Subproject: this is subproject number 002 , established and managed by the Center Director under grant R831861
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Southern California Children's Environmental Health Center
Center Director: McConnell, Rob Scot
Title: Pollution-Enhanced Allergic Inflammation and Phase II Enzymes
Investigators: Gilliland, Frank D. , Diaz-Sanchez, David
Institution: University of Southern California
EPA Project Officer: Callan, Richard
Project Period: November 1, 2003 through October 31, 2008 (Extended to October 31, 2010)
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2003) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The Children’s Environmental Health Center (CEHC) was established in 1998 to investigate effects of the environment on children’s respiratory health, with a focus on asthma and airway disease. The theme of the Center and its research focus were chosen based on the clinical and public health importance of childhood respiratory diseases and the potential importance of common environmental exposures on the etiology of these conditions, especially among susceptible subgroups of children. The Center also established a community outreach and translation program to translate research findings to communities and inform policymakers about the effects of the environment on children’s health.
Project 2: Pollution-Enhanced Allergic Inflammation and Phase II Enzymes
Specific Aims:
- We will test the hypothesis that Phase II enzyme expression in the upper airways are induced by oxidant pollutants and differ between children and adults.
- We will test the hypothesis that Phase II enzyme expression in the lower airways are induced by oxidant pollutants and differ between asthmatic and non-asthmatic subjects.
- We will determine the role of Phase II enzymes in regulating the adjuvant effects of PM.
Summary/Accomplishments (Outputs/Outcomes):
Aim 1
We had previously shown that challenge of individuals with diesel exhaust particles (DEP) induced GSTM1 expression in adults. We developed real-time quantitative PCR (RT-PCR) to measure gene expression of NQO1, GSTM1, GSTP1 and HO-1 from cells recovered from nasal washes. We recruited a total of 20 adult subjects and performed a double-blind randomized cross-over study to test the expression of these enzymes in response to nasal challenge with four different DEP doses (0, 30, 100, or 300 µg). Subjects performed nasal lavage sampling immediately before and 24 hours after each DEP challenge. DEP was administered by nasal spray into one nare via an atomizer. Each subject was randomized to one of 24 possible sequences of 4 DEP exposures. A four-week wash-out period was observed between each DEP exposure. All subjects had fully functional versions of GSTM1 and NQO1. The relative levels of gene expression were calculated after normalization to an internal control.
Figure 1. Relative levels of SGTP1 gene expression after normalization to an
internal control from 20 subject.
In each case, control expression (that seen in cells from lavages after challenge with saline) of the genes was given an arbitrary figure of 1.0 and relative expression calculated with reference to baseline. Figure 1 shows that expression of GSTP1 increased 24 hours after challenge with DEP. For nearly all subjects, there is a dose-response relationship between gene expression and the dose of DEP used in the nasal challenge. Similar results were observed in response to DEP challenge in expression of GSTM1, NQO1 and HO-1. While there was substantial inter-individual variation in the expression of any single enzyme, there was a very significant correlation between expression of all four enzymes, suggesting they are closely regulated. Cellular inflammation was measured in nasal lavages performed 24 hours after DEP challenge. As expected, there was a strong correlation between total cell number and the dose of DEP used in the nasal challenges. Moreover, total cell numbers were inversely correlated with expression of GSTP1 (p=0.03) and GSTM1 (p=0.04). DEP enhanced production of IL-8, TNF-α and GM-CSF in a dose-dependent fashion. Higher DEP challenge dose concentrations were associated with increased levels of chemokines.
Figure 2. GSTP1 response to DEP in adults vs. children
Figure 3. Cellular responses to DEP in adults vs. children
We expanded these studies and completed similar challenges in 20 children. In adults, DEP induced expression of GSTP1 in a dose-dependent fashion. With increasing concentrations of DEP challenge, there were higher levels of GSTP1-relative gene expression. Cellular infiltration was inversely correlated with GSTP1 enzyme gene expression. Increased levels of GSTP1 were associated with lower cell count numbers. In children, the degree of cellular infiltration also correlated with dose of nasally administered DEP challenge. Higher concentrations of DEP elicited a larger number of total cells recovered from nasal lavage fluid obtained 24 hours after DEP exposure. However, as compared to adults, this effect in children was more robust at the DEP challenge of 300 µg. In these children, DEP also induced expression of GSTP1. At DEP concentrations of 30 and 100 µg, there were higher levels of GSTP1-relative gene expression. However, GSTP1-relative gene expression for the DEP nasal challenge of 300 µg was decreased in children as compared to adults. Similar results were seen with the other three measured Phase II enzymes.
These results suggest that children appear to be more vulnerable to the adverse effects of oxidant pollutants, and they support the concept that the potential of an individual to mount a Phase II antioxidant defense may regulate the development of acute and chronic airway inflammation. We extended these studies to test whether in vitro Phase II enzyme expression can predict in vivo inflammatory responses to DEP. We recruited 20 allergic but otherwise healthy volunteers and obtained blood samples. We purified peripheral blood mononuclear cells (PBMNCs) from the subjects and stimulated the cells with 10 ug/mL of DEP in 1mL plates. After incubation for 24 hours, glutathione-S-transferase (GST) activity was measured by following the conjugation of 1mM 1-chloro-2,4,dintrochlorobenzene (CDNB) with 1mM GSH in 200mM sodium phosphate buffer as measured at 340nm using a spectrophotometer over time. Enzyme activity was expressed as millimoles of CDNB conjugated per minute per milligram of cytosolic protein. The subjects were then challenged intranasally with 300ug of DEP with nasal lavages performed prior and 24 hours after challenge.
Figure 4. In vitro GST activity predicts in vivo infammatory responses.
As seen in Figure 4, in vitro GST activity predicted in vivo inflammatory responses. The population could be divided into two populations: the first as those with a GST activity above 100 which had low or minimal inflammatory responses following DEP challenge. In this population (n=8), cell influx into the nose was limited and production of pro-inflammatory cytokines (GM-CSF, IL-1beta) and chemokines (RANTES, IL-8) was not statistically different after DEP challenges vs. baseline levels. The second population (n=12) had a GST activity under 60 and was characterized by a significant or very robust second inflammatory response following DEP challenge. In this population, there was a statistically significant increase in pro-inflammatory cytokines and chemokines after challenge. In addition, GST activity in this population was inversely proportional to cell numbers or RANTES production. Determining GST activity from blood cells may be a useful test to determine susceptibility to pollutants.
Aim 2
We exposed 20 healthy and 20 asthmatic subjects to diesel exhaust to study the effect of Phase II expression on lower airway responses. We could reproducibly produce a diesel particulate exposure level that was within 8% of the target level every time. These diesel particles are chemically and physically identical to diesel particles encountered in ambient air. Diesel exhaust resulted in increased expression of all four sentinel Phase II enzymes (GSTM1, GSTP1, HO-1 and NQO1) tested in cells recovered from sputum induced 24 hours after exposure to 2 hours of diesel exhaust (100 µg/m3). IL-8 levels in the sputum of subjects were significantly inversely correlated with Phase II expression. This increase was observed in both healthy and asthmatic subjects. There was wide heterogeneity in responses to DEP between subjects. While no enhanced inflammation was observed in any of the healthy subjects, four out of the twenty asthmatic subjects demonstrated a robust inflammatory response to DEP but not filtered air.
Aim 3
We have previously shown that enhancement of Phase II enzyme expression could inhibit enhancement of IgE production by peripheral blood cells in vitro. In those experiments, we used sulforaphane—a potent inducer of Phase II enzymes found in cruciferous vegetables. We tested whether this same reagent could block DEP-mediated adjuvant events in vivo in a murine model. Groups of six female BALB/c mice matched for age and weight (10-12 weeks) received aerosolized exposures to either saline, ovalbumin (OVA) (1% 20 min), DEP (1 hr) or OVA followed immediately by DEP for ten consecutive days. Mice were administered either vehicle (corn oil) or sulforaphane (4.5 µmol/mouse/day) by gavage (0.2 ml) for one week prior to the commencement of exposures up until two days after the last exposure. As expected, in the untreated group, IgG1 levels were significantly higher in mice who received both DEP and OVA than in those who were exposed to OVA alone. However, administration of sulforaphane completely ablated the adjuvant effects of DEP.
We then examined the responses of the airway epithelial cell line BEAS-2B and primary normal human bronchial epithelial cells upon treatment with sulforaphane and Phase II enzymes followed by stimulation with diesel extract (0-25 µg/ml). As expected, sulforaphane upregulated the expression of endogenous antioxidant enzymes in bronchial epithelial cells. Whereas diesel extract stimulated the production of IL-8, GM-CSF, and IL-1β from normal human bronchial epithelial cells, pre-treatment with sulforaphane for 24 hours inhibited diesel-induced cytokine production in a dose-dependent fashion. These studies suggest that sulforaphane treatment can prevent the production of pro-inflammatory cytokines in respiratory epithelial cells in vitro.
Previously, we reported that individuals who lack the ability to make the Phase II enzyme GSTM1 are at increased risk for the pro-inflammatory effects of DEP, and we have shown that enhancement of Phase II enzymes with sulforaphane can inhibit the production of pro-inflammatory cytokines in respiratory epithelial cells in vitro. In order to determine whether GSTM1 itself is important in the regulation of inflammatory response to pollutants, we used siRNA to “knock down” the GSTM1 gene in bronchial epithelial cells. Expression could be reduced by more than 90% using this methodology. Knockdown of GSTM1 augmented DEP induced cytokine production in these cells. Thus, IL-8 levels were almost three-fold higher in cells where GSTM1 expression was reduced, compared to sham-treated cells.
Finally, in a placebo-controlled dose escalation trial to investigate the in vivo effects of sulforaphane, we demonstrated that consumption of oral sulforaphane contained in broccoli sprouts homogenate (BSH) can induce a potent increase in antioxidant Phase II enzymes in airway cells. RNA expression for GSTM1, GSTP1, HO-1 and NQO1 was measured in nasal lavage cells by RT-PCR before and after sulforaphane dosing. Increased Phase II enzyme expression occurred in a dose-dependent manner with maximal enzyme induction observed at the highest dose of 200 g broccoli sprouts prepared as BSH. Significant increases were seen in all sentinel Phase II enzymes RNA expression compared to baseline. Phase II enzyme induction was not seen with ingestion of non-sulforaphane containing alfalfa sprouts. These findings suggest enhancement of Phase II enzyme expression as a novel therapeutic strategy for oxidant-induced airway disease.
Conclusions:
Our results show that Phase II enzymes can be induced by our model air pollutant, DEP, and are critical in regulating responses and determining susceptibility to these xenobiotics. A principal finding of our results is the discovery that children have enhanced inflammatory responses to the model pollutant DEP and that this seems to be related to their reduced capacity to make a cytoprotective Phase II enzymes response. Our studies illuminate why there may be increased susceptibility of certain vulnerable individuals and populations (such as children) to oxidant pollutants and suggest that increasing the body’s Phase II responses either by therapeutic or dietary means may counteract this effect. Moreover, the discovery that in vitro GST expression is associated with in vivo inflammatory responses provides the potential to develop a diagnostic test for susceptibility to oxidant pollutants.
Journal Articles on this Report : 89 Displayed | Download in RIS Format
| Other subproject views: | All 138 publications | 90 publications in selected types | All 89 journal articles |
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| Other center views: | All 202 publications | 132 publications in selected types | All 131 journal articles |
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Bastain TM, Islam T, Berhane KT, McConnell RS, Rappaport EB, Salam MT, Linn WS, Avol EL, Zhang Y, Gilliland FD. Exhaled nitric oxide, susceptibility and new-onset asthma in the Children’s Health Study. European Respiratory Journal 2011;37(3):523-531. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
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Berg J, McConnell R, Milam J, Galvan J, Kotlerman J, Thorne P, Jones C, Ferdman R, Eggleston P, Rand C, Lewis MA, Peters J, Richardson J. Rodent allergen in Los Angeles inner city homes of children with asthma. Journal of Urban Health 2008;85(1):52-61. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
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Berhane K, Gauderman WJ, Stram DO, Thomas DC. Statistical issues in studies of the long-term effects of air pollution: The Southern California Children's Health Study. Statistical Science 2004;19(3):414-449. |
R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
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Berhane K, Zhang Y, Linn WS, Rappaport EB, Bastain TM, Salam MT, Islam T, Lurmann F, Gilliland FD. The effect of ambient air pollution on exhaled nitric oxide in the Children’s Health Study. European Respiratory Journal 2011;37(5):1029-1036. |
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Breton CV, Vora H, Salam MT, Islam T, Wenten M, Gauderman WJ, Van den Berg D, Berhane K, Peters JM, Gilliland FD. Variation in the GST mu locus and tobacco smoke exposure as determinants of childhood lung function. American Journal of Respiratory and Critical Care Medicine 2009;179(7):601-607. |
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Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. American Journal of Respiratory and Critical Care Medicine 2009;180(5):462-467. |
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Breton CV, Salam MT, Vora H, Gauderman WJ, Gilliland FD. Genetic variation in the glutathione synthesis pathway, air pollution, and children’s lung function growth. American Journal of Respiratory and Critical Care Medicine 2011;183(2):243-248. |
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Conti DV, Gauderman WJ. SNPs, haplotypes, and model selection in a candidate gene region: the SIMPle analysis for multilocus data. Genetic Epidemiology 2004;27(4):429-441. |
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Cozen W, Avol E, Diaz-Sanchez D, McConnell R, Gauderman WJ, Cockburn MG, Zadnick J, Jyrala M, Mack TM. Use of an electrostatic dust cloth for self-administered home allergen collection. Twin Research and Human Genetics 2008;11(2):150-155. |
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Diaz-Sanchez D, Riedl M. Diesel effects on human health: a question of stress? American Journal of Physiology—Lung Cellular and Molecular Physiology 2005;289(5):L722-L723. |
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Diaz-Sanchez D, Rumold R, Gong Jr. H. Challenge with environmental tobacco smoke exacerbates allergic airway disease in human beings. Journal of Allergy and Clinical Immunology 2006;118(2):441-446. |
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Gauderman WJ, Avol E, Gilliland F, Vora H, Thomas D, Berhane K, McConnell R, Kuenzli N, Lurmann F, Rappaport E, Margolis H, Bates D, Peters J. The effect of air pollution on lung development from 10 to 18 years of age. New England Journal of Medicine 2004;351(11):1057-1067. |
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Gauderman WJ, Avol E, Lurmann F, Kuenzli N, Gilliland F, Peters J, McConnell R. Childhood asthma and exposure to traffic and nitrogen dioxide. Epidemiology 2005;16(6):737-743. |
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Gauderman WJ, Conti DV. Commentary: Models for longitudinal family data. International Journal of Epidemiology 2005;34(5):1077-1079. |
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Gauderman WJ. Air pollution and children — an unhealthy mix. New England Journal of Medicine 2006;355(1):78-79. |
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Gauderman WJ, Vora H, McConnell R, Berhane K, Gilliland F, Thomas D, Lurmann F, Avol E, Kunzli N, Jerrett M, Peters J. Effect of exposure to traffic on lung development from 10 to 18 years of age: a cohort study. Lancet 2007;369(9561):571-577. |
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Gauderman WJ, Murcray C, Gilliland F, Conti DV. Testing association between disease and multiple SNPs in a candidate gene. Genetic Epidemiology 2007;31(5):383-395. |
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Gilliland FD, Li Y-F, Saxon A, Diaz-Sanchez D. Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study. Lancet 2004;363(9403):119-125. |
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Gilliland FD, Li YF, Gong Jr. H, Diaz-Sanchez D. Glutathione s-transferases M1 and P1 prevent aggravation of allergic responses by secondhand smoke. American Journal of Respiratory and Critical Care Medicine 2006;174(12):1335-1341. |
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Gilliland FD, Islam T, Berhane K, Gauderman WJ, McConnell R, Avol E, Peters JM. Regular smoking and asthma incidence in adolescents. American Journal of Respiratory and Critical Care Medicine 2006;174(10):1094-1100. |
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Gilliland FD. Outdoor air pollution, genetic susceptibility, and asthma management: opportunities for intervention to reduce the burden of asthma. Pediatrics 2009;123(Suppl 3):S168-S173. |
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Gilliland F, Avol E, Kinney P, Jerrett M, Dvonch T, Lurmann F, Buckley T, Breysse P, Keeler G, de Villiers T, McConnell R. Air pollution exposure assessment for epidemiologic studies of pregnant women and children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research. Environmental Health Perspectives 2005;113(10):1447-1454. |
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Hricko A. Ships, trucks, and trains: effects of goods movement on environmental health. Environmental Health Perspectives 2006;114(4):A204-A205 (guest editorial). |
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Hricko A. Global trade comes home: community impacts of goods movement. Environmental Health Perspectives 2008;116(2):A78-A81. |
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Islam T, Gauderman WJ, Berhane K, McConnell R, Avol E, Peters JM, Gilliland FD. Relationship between air pollution, lung function and asthma in adolescents. Thorax 2007;62(11):957-963. |
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Islam T, Berhane K, McConnell R, Gauderman WJ, Avol E, Peters JM, Gilliland FD. Glutathione-S-transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children. Thorax 2009;64(3):197-202. |
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Islam T, Breton C, Salam MT, McConnell R, Wenten M, Gauderman WJ, Conti D, Van Den Berg D, Peters JM, Gilliland FD. Role of inducible nitric oxide synthase in asthma risk and lung function growth during adolescence. Thorax 2010; 65(2):139-145. |
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Jerrett M, Arain A, Kanaroglou P, Beckerman B, Potoglou D, Sahsuvaroglu T, Morrison J, Giovis C. A review and evaluation of intraurban air pollution exposure models. Journal of Exposure Analysis and Environmental Epidemiology 2005;15(2):185-204. |
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Jerrett M, Shankardass K, Berhane K, Gauderman WJ, Künzli N, Avol E, Gilliland F, Lurmann F, Molitor JN, Molitor JT, Thomas DC, Peters J, McConnell R. Traffic-related air pollution and asthma onset in children: a prospective cohort study with individual exposure measurement. Environmental Health Perspectives 2008;116(10):1433-1438. |
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Kanaroglou P, Jerrett M, Morrison J, Beckerman B, Arain A, Gilbert N, Brook J. Establishing an air pollution monitoring network for intra-urban population exposure assessment: a location-allocation approach. Atmospheric Environment 2005;39(13):2399-2409. |
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Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ. Exploiting gene-environment interaction to detect genetic associations. Human Heredity 2007;63(2):111-119. |
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Kunzli N, Perez L, Lurmann F, Hricko A, Penfold B, McConnell R. An attributable risk model for exposures assumed to cause both chronic disease and its exacerbations. Epidemiology 2008;19(2):179-185. |
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Lee YL, Gilliland FD, Wang JY, Lee YC, Guo YL. Associations of FcɛRIβ E237G polymorphism with wheezing in Taiwanese schoolchildren. Clinical & Experimental Allergy 2008;38(3):413-420. |
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Lee YL, McConnell R, Berhane K, Gilliland FD. Ambient ozone modifies the effect of tumor necrosis factor G-308A on bronchitic symptoms among children with asthma. Allergy 2009;64(9):1342-1348. |
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Li Y-F, Langholz B, Salam MT, Gilliland FD. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest 2005;127(4):1232-1241. |
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Li Y-F, Tsao YH, Gauderman WJ, Conti DV, Avol E, Dubeau L, Gilliland FD. Intercellular adhesion molecule-1 and childhood asthma. Human Genetics 2005;117(5):476-484. |
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Li Y-F, Gauderman WJ, Avol E, Dubeau L, Gilliland FD. Associations of tumor necrosis factor G-308A with childhood asthma and wheezing. American Journal of Respiratory and Critical Care Medicine 2006;173(9):970-976. |
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Linn WS, Avila M, Gong H Jr. Exhaled nitric oxide: sources of error in offline measurement. Archives of Environmental Health 2004;59(8):385-391. |
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Linn WS, Rappaport EB, Berhane KT, Bastain TM, Avol EL, Gilliland FD. Exhaled nitric oxide in a population-based study of southern California schoolchildren. Respiratory Research 2009;10(1):28. |
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Linn WS, Berhane KT, Rappaport EB, Bastain TM, Avol EL, Gilliland FD. Relationships of online exhaled, offline exhaled, and ambient nitric oxide in an epidemiologic survey of schoolchildren. Journal of Exposure Science & Environmental Epidemiology 2009;19(7):674-681. |
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Linn WS, Rappaport EB, Berhane KT, Bastain TM, Salam MT, Gilliland FD. Extended exhaled nitric oxide analysis in field surveys of schoolchildren: a pilot test. Pediatric Pulmonology 2009;44(10):1033-1042. |
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McConnell R, Berhane K, Molitor J, Gilliland F, Kunzli N, Thorne PS, Thomas D, Gauderman WJ, Avol E, Lurmann F, Rappaport E, Jerrett M, Peters JM. Dog ownership enhances symptomatic responses to air pollution in children with asthma. Environmental Health Perspectives 2006;114(12):1910-1915. |
R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (2007) R831861C003 (Final) R826708 (Final) R827352 (Final) R827352C007 (Final) |
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McConnell R, Berhane K, Yao L, Lurmann FW, Avol E, Peters JM. Predicting residential ozone deficits from nearby traffic. Science of the Total Environment 2006;363(1-3):166-174. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (2005) R831861C001 (2006) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R827352 (Final) R827352C007 (Final) |
Exit Exit Exit |
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McConnell R, Berhane K, Yao L, Jerrett M, Lurmann F, Gilliland F, Kunzli N, Gauderman J, Avol E, Thomas D, Peters J. Traffic, susceptibility, and childhood asthma. Environmental Health Perspectives 2006;114(5):766-772. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (2006) R831861C001 (Final) R831861C002 (Final) R831861C003 (2006) R831861C003 (2007) R831861C003 (Final) R826708 (Final) R827352 (Final) R827352C007 (Final) |
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McConnell R, Islam T, Shankardass K, Jerrett M, Lurmann F, Gilliland F, Gauderman J, Avol E, Kunzli N, Yao L, Peters J, Berhane K. Childhood incident asthma and traffic-related air pollution at home and school. Environmental Health Perspectives 2010;118(7):1021-1026. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R827352 (Final) |
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Milam J, McConnell R, Yao L, Berhane K, Jerrett M, Richardson J. Parental stress and childhood wheeze in a prospective cohort study. Journal of Asthma 2008;45(4):319-323. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Millstein J, Gilliland F, Berhane K, Gauderman WJ, McConnell R, Avol E, Rappaport EB, Peters JM. Effects of ambient air pollutants on asthma medication use and wheezing among fourth-grade school children from 12 Southern California communities enrolled in The Children's Health Study. Archives of Environmental Health 2004;59(10):505-514. |
R831861 (2006) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (2006) R831861C003 (Final) |
Exit |
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Millstein J, Siegmund KD, Conti DV, Gauderman WJ. Testing association and linkage using affected-sib-parent study designs. Genetic Epidemiology 2005;29(3):225-233. |
R831861 (2004) R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Millstein J, Conti DV, Gilliland FD, Gauderman WJ. A testing framework for identifying susceptibility genes in the presence of epistasis. American Journal of Human Genetics 2006;78(1):15-27. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (2006) R831861C003 (Final) |
Exit Exit Exit |
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Mirabelli MC, Kunzli N, Avol E, Gilliland FD, Gauderman WJ, McConnell R, Peters JM. Respiratory symptoms following wildfire smoke exposure: airway size as a susceptibility factor. Epidemiology 2009;20(3):451-459. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R831845 (2005) |
Exit |
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Molitor J, Molitor N-T, Jerrett M, McConnell R, Gauderman J, Berhane K, Thomas D. Bayesian modeling of air pollution health effects with missing exposure data. American Journal of Epidemiology 2006;164(1):69-76. |
R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R827352 (Final) R831845 (2005) |
Exit Exit |
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Molitor J, Jerrett M, Chang CC, Molitor NT, Gauderman J, Berhane K, McConnell R, Lurmann F, Wu J, Winer A, Thomas D. Assessing uncertainty in spatial exposure models for air pollution health effects assessment. Environmental Health Perspectives 2007;115(8):1147-1153. |
R831861 (Final) R831861C001 (2007) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
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Mueller-Anneling L, Avol E, Peters JM, Thorne PS. Ambient endotoxin concentrations in PM10 from Southern California. Environmental Health Perspectives 2004;112(5):583-588. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
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Murcray CE, Lewinger JP, Gauderman WJ. Gene-environment interaction in genome-wide association studies. American Journal of Epidemiology 2009;169(2):219-226. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit Exit |
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Perez L, Kunzli N, Avol E, Hricko AM, Lurmann F, Nicholas E, Gilliland F, Peters J, McConnell R. Global goods movement and the local burden of childhood asthma in southern California. American Journal of Public Health 2009;99(Suppl 3):S622-S628. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R831845 (2005) |
Exit |
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Riedl MA, Landaw EM, Saxon A, Diaz-Sanchez D. Initial high-dose nasal allergen exposure prevents allergic sensitization to a neoantigen. Journal of Immunology 2005;174(11):7440-7445. |
R831861 (2004) R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
Exit Exit |
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Riedl MA, Saxon A, Diaz-Sanchez D. Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clinical Immunology 2009;130(3):244-251. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Riedl M, Diaz-Sanchez D. Biology of diesel exhaust effects on respiratory function. Journal of Allergy and Clinical Immunology 2005;115(2):221-228. |
R831861 (2004) R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
Exit Exit Exit |
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Ritz SA, Wan J, Diaz-Sanchez D. Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract. American Journal of Physiology-Lung Cellular and Molecular Physiology 2007;292(1):L33-L39. |
R831861 (2006) R831861 (Final) R831861C001 (Final) R831861C002 (2006) R831861C002 (2007) R831861C002 (Final) R831861C003 (Final) |
Exit Exit Exit |
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Rondeau V, Berhane K, Thomas DC. A three-level model for binary time-series data: the effects of air pollution on school absences in the Southern California Children's Health Study. Statistics in Medicine 2005;24(7):1103-1115. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Ross Z, English PB, Scalf R, Gunier R, Smorodinsky S, Wall S, Jerrett M. Nitrogen dioxide prediction in Southern California using land use regression modeling: potential for environmental health analyses. Journal of Exposure Science and Environmental Epidemiology 2006;16(2):106-114. |
R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit |
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Salam MT, Li Y-F, Langholz B, Gilliland FD. Early-life environmental risk factors for asthma:findings from the Children's Health Study. Environmental Health Perspectives 2004;112(6):760-765. |
R831861 (2004) R831861 (2005) R831861 (Final) R831861C001 (2005) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
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Salam MT, Li Y-F, Langholz B, Gilliland FD. Maternal fish consumption during pregnancy and risk of childhood asthma. Journal of Asthma 2005;42(6):513-518. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (2006) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
Exit |
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Salam MT, Millstein J, Li YF, Lurmann FW, Margolis HG, Gilliland FD. Birth outcomes and prenatal exposure to ozone, carbon monoxide, and particulate matter: results from the Children's Health Study. Environment Health Perspectives 2005;113(11):1638-1644. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (2006) R831861C003 (Final) |
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Salam MT, Margolis HG, McConnell R, McGregor JA, Avol EL, Gilliland FD. Mode of delivery is associated with asthma and allergy occurrences in children. Annals of Epidemiology 2006;16(5):341-346. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (2006) R831861C001 (Final) R831861C002 (Final) R831861C003 (2006) R831861C003 (Final) |
Exit |
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Salam MT, Gauderman WJ, McConnell R, Lin PC, Gilliland FD. Transforming growth factor-β1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma. American Journal of Respiratory and Critical Care Medicine 2007;176(12):1192-1199. |
R831861 (Final) R831861C001 (2007) R831861C001 (Final) R831861C002 (Final) R831861C003 (2007) R831861C003 (Final) |
Exit Exit Exit |
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Salam MT, Lin PC, Avol EL, Gauderman WJ, Gilliland FD. Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma. Thorax 2007;62(12):1050-1057. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit Exit |
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Salam MT, Islam T, Gilliland FD. Recent evidence for adverse effects of residential proximity to traffic sources on asthma. Current Opinion in Pulmonary Medicine 2008;14(1):3-8. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Salam MT, Islam T, Gauderman WJ, Gilliland FD. Roles of arginase variants, atopy, and ozone in childhood asthma. Journal of Allergy and Clinical Immunology 2009;123(3):596-602. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
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Salam MT, Bastain TM, Rappaport EB, Islam T, Berhane K, Gauderman WJ, Gilliland FD. Genetic variations in nitric oxide synthase and arginase influence exhaled nitric oxide levels in children. Allergy 2011;66(3):412-419. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit |
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Sawant AA, Cocker III DR, Miller JW, Taliaferro T, Diaz-Sanchez D, Linn WS, Clark KW, Gong Jr. H. Generation and characterization of diesel exhaust in a facility for controlled human exposures. Journal of the Air & Waste Management Association 2008;58(6):829-837. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Saxon A, Diaz-Sanchez D. Air pollution and allergy: you are what you breathe. Nature Immunology 2005;6(3):223-226. |
R831861 (2004) R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
Exit Exit |
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Shankardass K, McConnell RS, Milam J, Berhane K, Tatalovich Z, Wilson JP, Jerrett M. The association between contextual socioeconomic factors and prevalent asthma in a cohort of Southern California school children. Social Science & Medicine 2007;65(8):1792-1806. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Stram DO. Designs for studies of personal exposure to air pollution and the impact of measurement error. Journal of Toxicology and Environmental Health, Part A 2005;68(13-14):1181-1187. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Stram DO. Software for tag single nucleotide polymorphism selection. Human Genomics 2005;2(2):144-151. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit Exit |
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Thomas DC. The need for a systematic approach to complex pathways in molecular epidemiology. Cancer Epidemiology Biomarkers & Prevention 2005;14(3):557-559. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit |
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Thomas DC, Haile RW, Duggan D. Recent developments in genomewide association scans: a workshop summary and review. American Journal of Human Genetics 2005;77(3):337-345. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Thomas DC, Witte JS, Greenland S. Dissecting effects of complex mixtures: who's afraid of informative priors? Epidemiology 2007;18(2):186-190. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Thomas D, Xie R, Gebregziabher M. Two-stage sampling designs for gene association studies. Genetic Epidemiology 2004;27(4):401-414. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Thomas D. Why do estimates of the acute and chronic effects of air pollution on mortality differ? Journal of Toxicology and Environmental Health, Part A 2005;68(13-14):1167-1174. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Thorne PS, Metwali N, Avol E, McConnell RS. Surface sampling for endotoxin assessment using electrostatic wiping cloths. Annals of Occupational Hygiene 2005;49(5):401-406. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (2006) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
Exit Exit Exit |
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Wan J, Diaz-Sanchez D. Phase II enzymes induction blocks the enhanced IgE production in B cells by diesel exhaust particles. Journal of Immunology 2006;177(5):3477-3483. |
R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (Final) R831861C002 (2006) R831861C002 (2007) R831861C002 (Final) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
Exit Exit |
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Wan J, Diaz-Sanchez D. Antioxidant enzyme induction: a new protective approach against the adverse effects of diesel exhaust particles. Inhalation Toxicology 2007;19(Suppl 1):177-182. |
R831861 (Final) R831861C001 (Final) R831861C002 (2007) R831861C002 (Final) R831861C003 (Final) |
Exit |
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Wang C, Salam MT, Islam T, Wenten M, Gauderman WJ, Gilliland FD. Effects of in utero and childhood tobacco smoke exposure and beta2-adrenergic receptor genotype on childhood asthma and wheezing. Pediatrics 2008;122(1):e107-e114. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit Exit |
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Wenten M, Berhane K, Rappaport EB, Avol E, Tsai WW, Gauderman WJ, McConnell R, Dubeau L, Gilliland FD. TNF-308 modifies the effect of second-hand smoke on respiratory illness-related school absences. American Journal of Respiratory and Critical Care Medicine 2005;172(12):1563-1568. |
R831861 (2004) R831861 (2005) R831861 (2006) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (2006) R831861C003 (Final) R826708 (2000) R826708 (2001) R826708 (2002) R826708 (Final) |
Exit Exit |
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Wenten M, Gauderman WJ, Berhane K, Lin PC, Peters J, Gilliland FD. Functional variants in the catalase and myeloperoxidase genes, ambient air pollution, and respiratory-related school absences: an example of epistasis in gene-environment interactions. American Journal of Epidemiology 2009;170(12):1494-1501. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit Exit |
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Wenten M, Li YF, Lin PC, Gauderman WJ, Berhane K, Avol E, Gilliland FD. In utero smoke exposure, glutathione S-transferase P1 haplotypes, and respiratory illness-related absence among schoolchildren. Pediatrics 2009;123(5):1344-1351. |
R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) |
Exit Exit Exit |
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Wu J, Lurmann F, Winer A, Lu R, Turco R, Funk T. Development of an individual exposure model for application to the Southern California Children's Health Study. Atmospheric Environment 2005;39(2):259-273. |
R831861 (2004) R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R827352 (Final) R827352C015 (Final) R828172 (Final) R831845 (2005) |
Exit Exit Exit |
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Wu J, Funk T, Lurmann F, Winer A. Improving spatial accuracy of roadway networks and geocoded addresses. Transactions in GIS 2005;9(4):585-601. |
R831861 (2005) R831861 (Final) R831861C001 (Final) R831861C002 (Final) R831861C003 (Final) R827352 (Final) R827352C015 (Final) R831845 (2005) |
Exit |
Supplemental Keywords:
Asthma, children, susceptibility, community, children’s health, health effects, risk assessment, airway disease, allergen, asthma, childhood respiratory disease, children’s environmental health, community-based intervention, outreach and education, respiratory problems, RFA, Health, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, HUMAN HEALTH, Health Risk Assessment, Health Effects, Biochemistry, Children's Health, Risk Assessment, asthma, community-based intervention, airway disease, respiratory problems, animal model, Human Health Risk Assessment, childhood respiratory disease, susceptibility, children's environmental health, outreach and educationProgress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R831861 Southern California Children's Environmental Health Center Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R831861C001 Urban Air Pollution and Persistent Early Life Asthma
R831861C002 Pollution-Enhanced Allergic Inflammation and Phase II Enzymes
R831861C003 Air Pollution, Exhaled Breath Markers, and Asthma in Susceptible Children
The 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.