Final Report: Endotoxin Exposure and Asthma in Children

EPA Grant Number: RD834515
Center: Denver Children’s Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Schwartz, David A.
Title: Endotoxin Exposure and Asthma in Children
Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Martyny, John W. , Murphy, Amy J , Rabinovitch, Nathan , Strand, Mathew J. , Van Dyke, Michael V.
Institution: National Jewish Health
EPA Project Officer: Louie, Nica
Project Period: June 22, 2010 through June 21, 2015 (Extended to June 21, 2017)
Project Amount: $1,897,209
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text |  Recipients Lists
Research Category: Children's Health , Health

Objective:

The mission of the Denver Children's Environmental Health Center (CEHC) was to investigate the etiology and pathogenesis of airway disease in children. This research is important for the following reasons:

• Asthma and other forms of airway disease/illness are the most common chronic illnesses in children.

• Children are susceptible to environmental exposures that affect lung immunity and can alter the risk of developing airway disease.

• Environmental models of airway disease provide an ideal opportunity to investigate the mechanisms involved in the development of childhood airway disease such as the basic immunology and persistence of airway disease.

• This research builds on existing scientific expertise and relationships with community stakeholders and members to ensure a highly interactive program.

The unifying hypothesis of our research program was that lung host defense and lung immunity are dynamic and are affected by ozone and endotoxin, and that this dynamic biology can alter susceptibility to agents known to cause airway disease in children. We focused on ozone and endotoxin in our program because they are common environmental exposures and have been shown to have immune modulating affects. We discovered ample clinical and laboratory based evidence that ozone, endotoxin, and other air pollutants can affect lung immunity and responses underlying airway disease and asthma in children. The novel scientific findings from our highly integrated Center enhanced our understanding of airway disease in children and were translated to communities in Colorado.

Project 1: Higher levels of endotoxin exposure cause persistent, problematic asthma, and key environmental (ozone and allergens) and genetic modifiers (endotoxin receptor polymorphisms) contribute to endotoxin susceptibility and pathological asthmatic responses.

Project 2: Ozone exposure in the early postnatal phase alters lung development and changes the host immune response to early life viral infection and allergen exposure, thereby contributing to the development of reactive airway disease.

Project 3: Expression of toll-like receptors (TLRs) in the lung are influenced by environmental (ozone and/or PAMPs) and genetic factors, and the dynamic expression of TLRs has profound effects on lung host defense and, consequently, the development of lung infections and allergic airway disease.

Summary/Accomplishments (Outputs/Outcomes):

Accomplishments

• We are the first, to our knowledge, to distinguish household endotoxin from mold exposure in children with asthma. By measuring endotoxin with the Recombinant Factor C (rFC) reagent specific for endotoxin (instead of the commonly used Limulus Amebocyte Lysate assay that detects both endotoxin and fungal glucans) and using separate mold exposure measures, we isolated the effects of household endotoxin and mold exposures on asthma severity. In an ancillary investigation to the Childhood Asthma Management Program (CAMP) study, we found that higher endotoxin levels in baseline dust samples (n=962) were associated with fewer prednisone days (an indicator of severe asthma exacerbations), while high mold counts were associated with more prednisone days during the 4-year course of the study. When the effects of endotoxin and mold exposures on prednisone days were assessed for each site, endotoxinassociated reductions and mold-associated increases in prednisone days were found for 5 of the 8 sites, consistent with the overall model. 

• In an ancillary investigation to the CAMP study, we investigated the interaction of endotoxin with 48 single nucleotide polymorphisms (SNPs) in 11 Toll-Like Receptor (TLR) genes (TLR-1, - 2, -3, -4, -5, -6, -9, -10, CD14, MyD88, LY96, ACAA1) on severe asthma exacerbations (i.e., at least one ER visit or hospitalization for asthma in the past year). This preliminary analysis was restricted to Caucasian participants. Of these 517 participants, 84 were cases with at least one severe asthma exacerbation, and 433 were controls. For two SNPs (in TLR9 and MyD88), higher endotoxin levels (log-transformed) increased the risk of severe asthma exacerbations. Because of these significant TLR gene-endotoxin interactions, we expanded our genotyping of genes downstream of the TLR receptor complex. We found endotoxin interactions with gene polymorphisms in SPTLC2, ASAH1, GALC, ARSB, PPAP2B, and SPTLC1 that contributed to glycosphingolipid pathway enrichment. These gene-by-environment interactions would not have been detected in a conventional genome wide survey of individual SNP-level gene-by-environment associations. Published in Am J Resp Crit Care Med 2014 189:A3835.

• In an ancillary investigation to the Healthy Homes Demonstration study sponsored by the Department of Housing and Urban Development, we collected 262 house dust samples in 70 homes and found that remediation did not significantly reduce house dust endotoxin levels.

• In an ancillary investigation to the Mouse Allergen and Asthma Cohort Study (PI - EC Matsui, JHI CEHC), we investigated the interaction of endotoxin with home air pollutants in 150 Baltimore urban children with asthma. With low air nicotine exposure, higher endotoxin (again measured with the endotoxin-specific rFC assay) was inversely associated with acute visits and oral corticosteroid bursts for severe exacerbations. In contrast, in homes with detectable air nicotine, endotoxin was positively associated with these outcomes (interaction P values 0.004 for acute visits and 0.07 for oral steroid bursts). Among children living in homes with lower NO2 concentrations (<20 ppb), higher endotoxin was positively associated with acute visits; in contrast, in homes with higher NO2 concentrations, endotoxin was negatively associated with acute visits (interaction P value 0.05). Particulate matter did not modify endotoxin’s effects on asthma severity. These findings highlight the importance of interpreting the effects of endotoxin on asthma in the context of coexposure to cigarette smoke and NO2.

• In our Endotoxin Personal Monitoring (EPEM) pilot study and Denver Asthma Panel Study (DAPS) of children with exacerbation-prone asthma, we successfully used personal and stationary monitors to measure particulate matter less than ten microns in diameter (PM10), nitrogen dioxide (NO2), ozone, black carbon, brown carbon, environmental tobacco smoke (ETS), and position (via a small GPS receiver). We obtained very accurate personal exposure data, because participants achieved a high level of wearing compliance with a median percent monitored time of 89%. Preliminary analyses found that personal environmental exposures (ETS and NO2) were associated with clinical asthma assessments and inflammatory markers whereas bedroom and outdoor exposure measurements did not. Using real-time PM10 and GPS data we mapped spikes in PM10 exposure and found that most exposures occurred at home while the participants were awake.

• To determine if gene expression in the airway was influenced by specific exposures, we instilled LPS, house dust mite (HDM) antigen, and saline in three sub-segmental bronchi and measured gene expression in the airway epithelia 4 hours following the instillation. We found that among subjects with allergic asthma, transcriptional changes in airway epithelia and inflammatory cells were substantially affected by environmental exposures, such as LPS and, to a much smaller extent, HDM antigen.  

• We profiled the transcriptome response of the newborn mouse lung to acute ozone exposure using genome-wide gene expression microarray analysis. The results identified several novel genes and molecular pathways never before associated with ozone exposure. It is not clear whether this suppression of the cell cycle/proliferation can lead to permanent damage to the lung (altered lung growth or altered structure and function) or if it is transient only, allowing repair of potentially damaged DNA from ozone exposure.

• Neonatal mice, compared to adult mice, expressed low levels of pulmonary TLR4 but responded with increased mucus production. The neonatal mice developed an attenuated response to ozone characterized by reduced albumin leakage and reduced neutrophils influx into the airways, which was associated with lower expression of neutrophilic chemokines CXCL1 and CXCL2. This shows that the response to ozone is determined by age and is partially dependent on TLR4 signaling, and suggests that the reduced responsiveness of the neonatal lung to ozone could be due to insufficient expression of pulmonary TLR4.

• Effects of ozone and RSV in neonatal mice demonstrate that following postnatal ozone exposure, the cytokine responses to either the primary or secondary RSV infection were not altered significantly. These findings are similar to those obtained for HDM allergen exposure and further suggest that ozone may promote the development of reactive airway disease in response to common triggers (RSV or allergen) through a common pathway that requires increased sensitization or inflammation.

• In adult mouse lung, ozone pre-exposure, alone or in combination with Pam3CYS (a TLR2/TLR6 agonist), resulted in increased whole lung lavage cell influx, increased IL-6 and KC, decreased MIP-1α and TNF-α, and increased cell surface expression of TLR4, TLR2, and TLR1 on macrophages. In addition, we demonstrated that ozone followed by Pam3CYS resulted in a large increase in phosphorylation of both p44/42 mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinases (JNK) and in significant reduction of non-phosphorylated p44/42 MAPK at 4 hours post Pam3CYS. This enhanced signal associated with ozone/Pam3CYS treatment was not present at 24 hours. Ozone pre-exposure prior to Pam3CYS treatment (O3/Pam3CYS vs. filtered air (FA)/Pam3CYS) enhanced induction of transfer RNA methyltransferase 5 at 4 hours and cholecystokinin at 24 hours. Expression of TTK protein kinase (4-hour time point) and phosphatidylethanolamine-binding protein 2, gap junction protein beta 4, non-SMC condensin I complex subunit G, and PDZ-binding kinase (24-hour time point) was also increased in the O3/Pam3CYS vs. FA/Pam3CYS but was significantly less than in the O3/saline vs. FA/saline comparison. The most significant result among downregulated genes was down-regulation at 24 hours of killer cell lectin-like receptors (Klra3, Klra8, Klra9, Klra10, Klra15, Klra21, Klra22, Klra23, Klrb1a, and Klrk1). Our study demonstrated that expression of TLRs on macrophage surface is a dynamic process that is influenced by ozone and that this process is associated with differential expression of a number of previously unexplored genes. 

• Although it had been established that expression of macrophage receptor with collagenous structure (MARCO) and phagocytosis is increased in tolerant macrophages, the transcriptional regulation and biological role of MARCO in tolerant macrophages had not been investigated. We confirmed that tolerized mouse bone marrow derived macrophages (BMDM) selectively increase expression of MARCO (both transcript and cell surface receptor) and increase phagocytosis. We found that H3K4me3 dynamic modification of a promoter site of MARCO was increased in tolerized BMDM. Blocking methylation by treatment with 5-Aza-2ʹ- deoxycytidine (5-AZA) resulted in reduced H3K4me3 binding in the promoter of MARCO, decreased expression of MARCO, and impaired phagocytosis in tolerized BMDM. However, 5-AZA had no effect on the inflammatory component of innate immune tolerance. In aggregate, we found that histone methylation was critical to MARCO expression and phagocytosis in tolerized macrophages but did not affect the inflammatory component of innate immune tolerance. 

• To understand how epigenetic mechanisms alter dendritic cell (DC) function and contribute to the etiology of allergic airway disease, we developed a line of investigation that examined epigenetic marks and transcriptional profiles in distinct lineages (CD11b+ or CD103+) of DCs that exist within the lung and are recruited to the draining lymph nodes in response to allergic sensitization. CD11b+ and CD103+ DC subsets were exposed to fluorescently labeled house dust mite or cockroach allergens in the lung and then isolated from draining lymph nodes. Transcriptional analysis revealed 768 and 1044 differentially expressed genes in the allergen-treated CD11b+ and CD103+ DCs, respectively, compared to saline controls.
 

Conclusions:

Benefit to the Environment and Human Health

Our research has helped the environment and human health by increasing scientific knowledge, educating the community, and empowering future research in the following ways:

• Endotoxin, mold, NO2 (a potentially harmful gas), and tobacco smoke are common environmental exposures known to have an effect on human health. We demonstrated the feasibility and importance of using an endotoxin-specific assay to assess this exposure in dust and airborne samples. We found that these exposures impact future exacerbation risk in children with asthma. We also found that variations in two genes (TLR9 and MYD88) increased the risk of severe asthma exacerbations if a person was exposed to higher endotoxin levels. Both of these findings provide a foundation for taking preventive measures to lower the risk of asthma exacerbations.

• We found that personal air monitors are a feasible and accurate way to measure pollution exposure in children. This finding paves the way for future monitoring to improve our understanding of how environmental exposures affect human health. The personal nature of the monitoring means that treatments and interventions can be tailored to the individual.

• Ozone is a gas that can be harmful to human health. Our research improved scientific knowledge about how ozone affects lung biology and the immune system. We discovered new ways that lungs react to ozone exposure and how changes depend on the age of the individual. Understanding how ozone causes problems provides opportunities for future research, treatment, and prevention.

• Through the COTC, we were able to educate the community about human health and the environment. All Center investigators presented their research at the Air Quality Symposium, “How Does Air Quality Affect Health?” This conference was attended by community stakeholders, including industrial hygienists, local and rural public health departments, and school personnel. We developed Air Quality Fact Sheets for particulate matter, pesticides, and ozone to help community members understand and protect themselves from these environmental hazards. Our Clean Air Projects website (www.capk-12.org) continues to provide environmental education related to air quality that is engaging and relevant. This information encourages youth and educators to become critical thinkers capable of making informed decisions and taking actions to improve air quality and health. The website also holds many resources related to health and air quality for the community, including the Air Quality Fact Sheets and presentations by Center investigators.

• The New Investigator Grants provided by the Center supported new investigators interested in studying the environment and human health. Empowering the next generation of scientists to research human health ensures future progress and benefit to both human and environmental health.


Journal Articles: 31 Displayed | Download in RIS Format

Other center views: All 51 publications 30 publications in selected types All 30 journal articles
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Journal Article Alper S, Warg LA, De Arras L, Flatley BR, Davidson EJ, Adams J, Smith K, Wohlford-Lenane CL, McCray Jr PB, Pedersen BS, Schwartz DA, Yang IV. Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria. Genetics 2016;204(1):327-336. RD834515 (Final)
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  • Journal Article Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. Small-magnitude effect sizes in epigenetic end points are important in children's environmental health studies: the Children's Environmental Health and Disease Prevention Research Center's Epigenetics Working Group. Environmental Health Perspectives 2017;125(4):511-526. RD834515 (Final)
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  • Journal Article Das R, Subrahmanyan L, Yang IV, van Duin D, Levy R, Piecychna M, Leng L, Montgomery RR, Shaw A, Schwartz DA, Bucala R. Functional polymorphisms in the gene encoding macrophage migration inhibitory factor are associated with gram-negative bacteremia in older adults. Journal of Infectious Diseases 2014;209(5):764-768. RD834515 (2013)
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  • Journal Article De Arras L, Seng A, Lackford B, Keikhaee MR, Bowerman B, Freedman JH, Schwartz DA, Alper S. An evolutionarily conserved innate immunity protein interaction network. Journal of Biological Chemistry 2013;288(3):1967-1978. RD834515 (2013)
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  • Journal Article Gabehart K, Correll KA, Yang J, Collins ML, Loader JE, Leach S, White CW, Dakhama A. Transcriptome profiling of the newborn mouse lung response to acute ozone exposure. Toxicological Sciences 2014;138(1):175-190. RD834515 (2011)
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  • Journal Article Gabehart K, Correll KA, Loader JE, White CW, Dakhama A. The lung response to ozone is determined by age and is partially dependent on toll-like receptor 4. Respiratory Research 2015;16:117. RD834515 (2013)
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  • Journal Article Gao Z, Dosman JA, Rennie DC, Schwartz DA, Yang IV, Beach J, Senthilselvan A. NOS3 polymorphism, lung function, and exposure in swine operations: results of 2 studies. Journal of Allergy and Clinical Immunology 2014;134(2):485-488. RD834515 (2013)
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  • Journal Article Henao-Martinez AF, Agler AH, LaFlamme D, Schwartz DA, Yang IV. Polymorphisms in the SUFU gene are associated with organ injury protection and sepsis severity in patients with Enterobacteriacea bacteremia. Infection, Genetics and Evolution 2013;16:386-391. RD834515 (2013)
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  • Journal Article Jing J, Yang IV, Hui L, Patel JA, Evans CM, Prikeris R, Kobzik L, O'Connor BP, Schwartz DA. Role of macrophage receptor with collagenous structure in innate immune tolerance. Journal of Immunology 2013;190(12):6360-6367. RD834515 (2013)
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  • Journal Article Kelada SN, Wilson MS, Tavarez U, Kubalanza K, Borate B, Whitehead GS, Maruoka S, Roy MG, Olive M, Carpenter DE, Brass DM, Wynn TA, Cook DN, Evans CM, Schwartz DA, Collins FS. Strain-dependent genomic factors affect allergen-induced airway hyperresponsiveness in mice. American Journal of Respiratory Cell and Molecular Biology 2011;45(4):817-824. RD834515 (2013)
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  • Journal Article Lai PS, Hofmann O, Baron RM, Cernadas M, Meng QR, Bresler HS, Brass DM, Yang IV, Schwartz DA, Christiani DC, Hide W. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin. PLoS One 2013;8(5):e62910. RD834515 (2013)
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  • Journal Article Long H, O'Connor BP, Zemans RL, Zhou X, Yang IV, Schwartz DA. The Toll-like receptor 4 polymorphism Asp299Gly but not Thr399Ile influences TLR4 signaling and function. PLoS One 2014;9(4):e93550 (10 pp.). RD834515 (2013)
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  • Journal Article Matsui EC, Hansel NN, Aloe C, Schiltz AM, Peng RD, Rabinovitch N, Ong MJ, Williams DL, Breysse PN, Diette GB, Liu AH. Indoor pollutant exposures modify the effect of airborne endotoxin on asthma in urban children. American Journal of Respiratory and Critical Care Medicine 2013;188(10):1210-1215. RD834515 (2012)
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  • Journal Article Oakes JL, O'Connor BP, Warg LA, Burton R, Hock A, Loader J, LaFlamme D, Jing J, Hui L, Schwartz DA, Yang IV. Ozone enhances pulmonary innate immune response to a Toll-like receptor-2 agonist. American Journal of Respiratory Cell and Molecular Biology 2013;48(1):27-34. RD834515 (2013)
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  • Journal Article Szefler SJ, Dakhama A. New insights into asthma pathogenesis and treatment. Current Opinion in Immunology 2011;23(6):801-807. RD834515 (2011)
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  • Journal Article Szefler SJ. Advancing asthma care: the glass is only half full! Journal of Allergy and Clinical Immunology 2011;128(3):485-494. RD834515 (2011)
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  • Journal Article Szefler SJ. Advances in pediatric asthma in 2011: moving forward. Journal of Allergy and Clinical Immunology 2012;129(1):60-68. RD834515 (2011)
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  • Journal Article Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. RD834515 (2013)
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  • Journal Article Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012; 303(5):L391-L400.. RD834515 (Final)
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  • Journal Article Warg LA, Oakes JL, Burton R, Neidermyer AJ, Rutledge HR, Groshong S, Schwartz DA, Yang IV. The role of the E2F1 transcription factor in the innate immune response to systemic LPS. American Journal of Physiology-Lung Cellular and Molecular Physiology 2012;303(5):L391-L400. RD834515 (2013)
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  • Journal Article Yang IV, Alper S, Lackford B, Rutledge H, Warg LA, Burch LH, Schwartz DA. Novel regulators of the systemic response to lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology 2011;45(2):393-402. RD834515 (2013)
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  • Journal Article Yang IV, Tomfohr J, Singh J, Foss CM, Marshall HE, Que LG, McElvania-Tekippe E, Florence S, Sundy JS, Schwartz DA. The clinical and environmental determinants of airway transcriptional profiles in allergic asthma. American Journal of Respiratory and Critical Care Medicine 2012;185(6):620-627. RD834515 (Final)
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  • Journal Article Julian CG, Yang IV, Browne VA, Vargas E, Rodriguez C, Pedersen BS, Moore LG, Schwartz DA. Inhibition of peroxisome proliferator-activated receptor gamma: a potential link between chronic maternal hypoxia and impaired fetal growth. FASEB Journal 2014;28(3):1268-1279. RD834515 (Final)
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  • Journal Article Kelada SN, Carpenter DE, Aylor DL, Chines P, Rutledge H, Chesler EJ, Churchill GA, Pardo-Manuel de Villena F, Schwartz DA, Collins FS. Integrative genetic analysis of allergic inflammation in the murine lung. American Journal of Respiratory Cell and Molecular Biology 2014;51(3):436-445. RD834515 (Final)
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  • Journal Article Liang L, Willis-Owen SAG, Laprise C, Wong KCC, Davies GA, Hudson TJ, Binia A, Hopkin JM, Yang IV, Grundberg E, Busche S, Hudson M, Ronnblom L, Pastinen TM, Schwartz DA, Lathrop GM, Moffatt MF, Cookson W. An epigenome-wide association study of total serum immunoglobulin E concentration. Nature 2015;520(7549):670-674. RD834515 (Final)
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  • Journal Article Eyring KR, Pedersen BS, Yang IV, Schwartz DA. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome. PloS one 2015;10(12):e0144087 (10 pp.). RD834515 (Final)
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  • Journal Article Julian CG, Pedersen BS, Salmon CS, Yang IV, Gonzales M, Vargas E, Moore LG, Schwartz DA. Unique DNA Methylation Patterns in Offspring of Hypertensive Pregnancy. Clinical and Translational Science 2015;8(6):740-745. RD834515 (Final)
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  • Journal Article Yang IV, Pedersen BS, Liu A, O’Connor GT, Teach SJ, Kattan M, Misiak RT, Gruchalla R, Steinbach SF, Szefler SJ, Gill MA, Calatroni A, David G, Hennessy CE, Davidson EJ, Zhang W, Gergen P, Togias A, Busse WW, Schwartz DA. DNA methylation and childhood asthma in the inner city. Journal of Allergy and Clinical Immunology 2015;136(1):69-80. RD834515 (Final)
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  • Journal Article Lai PS, Liang L, Cibas ES, Liu AH, Gold DR, Baccarelli A, Phipatanakul W. Alternate methods of nasal epithelial cell sampling for airway genomic studies. Journal of Allergy and Clinical Immunology 2015;136(4):1120-1123.e4. RD834515 (Final)
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  • Journal Article Yang IV, Richards A, Davidson EJ, Stevens AD, Kolakowski CA, Martin RJ, Schwartz DA. The nasal methylome: a key to understanding allergic asthma. American Journal of Respiratory and Critical Care Medicine 2017;195(6):829-831. RD834515 (Final)
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  • Journal Article Yang IV, Pedersen BS, Liu AH, O'Connor GT, Pillai D, Kattan M, Misiak RT, Gruchalla R, Szefler SJ, Khurana Hershey GK, Kercsmar C, Richards A, Stevens AD, Kolakowski CA, Makhija M, Sorkness CA, Krouse RZ, Visness C, Davidson EJ, Hennessy CE, Martin RJ, Togias A, Busse WW, Schwartz DA. The nasal methylome and childhood atopic asthma. Journal of Allergy and Clinical Immunology 2017;139(5):1478-1488. RD834515 (Final)
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  • Supplemental Keywords:

    RFA, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Children's Health, Biology, asthma, asthma triggers, sensitive populations, endotoxin, asthma indices, airway inflammation, children, allergic response

    Progress and Final Reports:

    Original Abstract
  • 2010 Progress Report
  • 2011 Progress Report
  • 2012 Progress Report
  • 2013 Progress Report
  • 2014 Progress Report
  • 2015 Progress Report
  • Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    RD834515C001 Endotoxin Exposure and Asthma in Children
    RD834515C002 Environmental Determinants of Early Host Response to RSV
    RD834515C003 Environmental Determinants of Host Defense