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1.  AllerGen’s 8th research conference 
Arrieta, Marie-Claire | Arevalos, Andrea | Stiemsma, Leah | Chico, Marta E. | Sandoval, Carlos | Jin, Minglian | Walter, Jens | Cooper, Phil | Finlay, Brett | Bernatchez, Emilie | Gold, Matthew J. | Langlois, Anick | Blais-Lecours, Pascale | Duchaine, Caroline | Marsolais, David | McNagny, Kelly M. | Blanchet, Marie-Renée | Brubacher, Jordan | Chhetri, Bimal | Sabaliauskas, Kelly | Bassil, Kate | Kwong, Jeff | Coates, Frances | Takaro, Tim K. | Chow, Angela | Miller, Gregory E. | Chen, Edith | Mandhane, Piushkumar J. | Turvey, Stuart E. | Elliott, Susan J. | Becker, Allan B. | Subbarao, Padmaja | Sears, Malcolm R. | Kozyrskyj, Anita L. | Dubeau, Aimée | Lu, Zihang | Balkovec, Susan | Kowalik, Krzysztof | Gustafsson, Per | Ratjen, Felix | Edgar, Rachel D. | Bush, Nicole R. | MacIssac, Julie L. | McEwen, Lisa M. | Boyce, Thomas W. | Kobor, Michael S. | Emmerson, Melanie | Dubeau, Aimée | Lu, Zihang | Shen, Bingqing | Kowalik, Krzysztof | Ratjen, Felix | Moraes, Theo J. | Gabrielli, Sofianne | Clarke, Ann | Eisman, Harley | Morris, Judy | Joseph, Lawrence | LaVieille, Sebastien | Ben-Shoshan, Moshe | Islam, Sumaiya A. | Brückmann, Christof | Nieratschker, Vanessa | Jamieson, Kyla C. | Proud, David | Kanagaratham, Cynthia | Camateros, Pierre | Kopriva, Frantisek | Henri, Jennifer | Hajduch, Marian | Radzioch, Danuta | Kang, Liane J. | Koleva, Petya T. | Field, Catherine J. | Konya, Tedd | Scott, James A. | Konya, Theodore | Azad, Meghan B. | Brook, Jeff | Guttman, David | Kumari, Manjeet | Bridgman, Sarah L. | Tun, Mon H. | Mandal, Rupasri | Wishart, David S. | Lee, Amy H. Y. | Xia, Jeff | Gill, Erin | Hancock, Bob | Maestre, Danay | Sutherland, Darren | Hirota, Jeremy | Pena, Olga | Carlsten, Christopher | McEwen, Lisa M. | Jones, Meaghan J. | MacIsaac, Julia L. | Dow, William H. | Rosero-Bixby, Luis | Rehkopf, David H. | Morimoto, Takeshi | Smith, Steven G. | Oliveria, John-Paul | Beaudin, Suzanne | Schlatman, Abbey | Howie, Karen | Obminski, Caitlin | Nusca, Graeme | Sehmi, Roma | Gauvreau, Gail M. | O’Byrne, Paul M. | North, Michelle | Peng, Cheng | Sanchez-Guerra, Marco | Byun, Hyang-Min | Ellis, Anne K. | Baccarelli, Andrea A. | Okeme, Joseph O. | Dhal, Suman | Saini, Aman | Diamond, Miriam L. | Olesovsky, Christopher J. | Salter, Brittany M. | Wang, Michael | Lacy, Paige | O’Sullivan, Michael J. | Park, Chan Y. | Fredberg, Jeffrey J. | Lauzon, Anne-Marie | Martin, James G. | Ryu, Min Hyung | Mookherjee, Neeloffer | Carlsten, Christopher | Simons, Elinor | Lefebvre, Diana | Dai, David | Singh, Amrit | Shannon, Casey P. | Kim, Young Woong | Yang, Chen Xi | Mark FitzGerald, J. | Boulet, Louis-Philippe | Tebbutt, Scott J. | Singhera, Gurpreet K. | JasemineYang, S. | Dorscheid, Delbert R. | Sinnock, Hasantha | Goruk, Susan | Tavakoli, Hamid | Lynd, Larry D. | Sadatsafavi, Mohsen | Tenn, Mark W. | Thiele, Jenny | Adams, Daniel E. | Steacy, Lisa M. | Ellis, Anne K. | Torabi, Bahar | De Schryver, Sarah | Lejtenyi, Duncan | Baerg, Ingrid | Chan, Edmond S. | Mazer, Bruce D. | Tran, Maxwell M. | Dai, Wei Hao | Lou, Wendy | Chari, Radha S. | Conway, Edward M. | Neighbour, Helen | Larché, Mark | Tebbutt, Scott J
PMCID: PMC5260783
2.  An Official American Thoracic Society Workshop Report: Presentations and Discussion of the Sixth Jack Pepys Workshop on Asthma in the Workplace 
The Sixth Jack Pepys Workshop on Asthma in the Workplace focused on six key themes regarding the recognition and assessment of work-related asthma and airway diseases: (1) cleaning agents and disinfectants (including in swimming pools) as irritants and sensitizers: how to evaluate types of bronchial reactions and reduce risks; (2) population-based studies of occupational obstructive diseases: use of databanks, advantages and pitfalls, what strategies to deal with biases and confounding?; (3) damp environments, dilapidated buildings, recycling processes, and molds, an increasing problem: mechanisms, how to assess causality and diagnosis; (4) diagnosis of occupational asthma and rhinitis: how useful are recombinant allergens (component-resolved diagnosis), metabolomics, and other new tests?; (5) how does exposure to gas, dust, and fumes enhance sensitization and asthma?; and (6) how to determine probability of occupational causality in chronic obstructive pulmonary disease: epidemiological and clinical, confirmation, and compensation aspects. A summary of the presentations and discussion is provided in this proceedings document. Increased knowledge has been gained in each topic over the past few years, but there remain aspects of controversy and uncertainty requiring further research.
PMCID: PMC5745582  PMID: 28862493
3.  Comparison of weighting approaches for genetic risk scores in gene-environment interaction studies 
BMC Genetics  2017;18:115.
Weighted genetic risk scores (GRS), defined as weighted sums of risk alleles of single nucleotide polymorphisms (SNPs), are statistically powerful for detection gene-environment (GxE) interactions. To assign weights, the gold standard is to use external weights from an independent study. However, appropriate external weights are not always available. In such situations and in the presence of predominant marginal genetic effects, we have shown in a previous study that GRS with internal weights from marginal genetic effects (“GRS-marginal-internal”) are a powerful and reliable alternative to single SNP approaches or the use of unweighted GRS. However, this approach might not be appropriate for detecting predominant interactions, i.e. interactions showing an effect stronger than the marginal genetic effect.
In this paper, we present a weighting approach for such predominant interactions (“GRS-interaction-training”) in which parts of the data are used to estimate the weights from the interaction terms and the remaining data are used to determine the GRS. We conducted a simulation study for the detection of GxE interactions in which we evaluated power, type I error and sign-misspecification. We compared this new weighting approach to the GRS-marginal-internal approach and to GRS with external weights.
Our simulation study showed that in the absence of external weights and with predominant interaction effects, the highest power was reached with the GRS-interaction-training approach. If marginal genetic effects were predominant, the GRS-marginal-internal approach was more appropriate. Furthermore, the power to detect interactions reached by the GRS-interaction-training approach was only slightly lower than the power achieved by GRS with external weights. The power of the GRS-interaction-training approach was confirmed in a real data application to the Traffic, Asthma and Genetics (TAG) Study (N = 4465 observations).
When appropriate external weights are unavailable, we recommend to use internal weights from the study population itself to construct weighted GRS for GxE interaction studies. If the SNPs were chosen because a strong marginal genetic effect was hypothesized, GRS-marginal-internal should be used. If the SNPs were chosen because of their collective impact on the biological mechanisms mediating the environmental effect (hypothesis of predominant interactions) GRS-interaction-training should be applied.
Electronic supplementary material
The online version of this article (10.1186/s12863-017-0586-3) contains supplementary material, which is available to authorized users.
PMCID: PMC5732390  PMID: 29246113
Polygenic approach; Training dataset; Internal weights; External weights; Simulation study; Power; Type I error
4.  A qualitative study of the knowledge, attitudes, and behaviors of people exposed to diesel exhaust at the workplace in British Columbia, Canada 
PLoS ONE  2017;12(8):e0182890.
To identify exposure-related knowledge, attitudes and behaviors of individuals occupationally exposed to diesel exhaust (DE); to reveal strengths, knowledge gaps and misperceptions therein.
A Mental Models approach was used to gather information about current scientific understanding of DE exposure hazards and the ways in which exposure can be reduced. Thirty individuals in British Columbia who were regularly exposed to occupational DE were interviewed. The audio was recorded and transcribed. Data was grouped together and examined to draw out themes around DE awareness, hazard assessment and risk reduction behaviors. These themes were then compared and contrasted with existing grey and research literature in order to reveal strengths, gaps and misperceptions regarding DE exposure.
Study participants were aware and concerned about their exposure to DE but had incomplete and sometimes incorrect understanding of exposure pathways, health effects, and effective strategies to reduce their exposures. The perceived likelihood of exposure to DE was significantly greater compared to that of other work hazards (p<0.01), whereas the difference for their perceived severity of consequences was not significant. There was no universally perceived main source of information regarding DE, and participants generally distrusted sources of information based on their past experience with the source. Most of the actions that were taken to address DE exposure fell into the area of administrative controls such as being aware of sources of DE and avoiding these sources.
This study of the knowledge, attitude, and behavior of those occupationally exposed to DE found, most notably, that more education and training and the creation of a health effects inventory regarding DE exposure were desired.
PMCID: PMC5571928  PMID: 28841707
5.  Canadian Society of Allergy and Clinical Immunology annual scientific meeting 2016 
Alsayegh, Mohammad A. | Alshamali, Hanan | Khadada, Mousa | Ciccolini, Amanda | Ellis, Anne K. | Quint, Diana | Powley, William | Lee, Laurie | Fiteih, Yahya | Baksh, Shairaz | Vliagoftis, Harissios | Gerega, Sebastien K. | Millson, Brad | Charland, Katia | Barakat, Stephane | Sun, Xichun | Jimenez, Ricardo | Waserman, Susan | FitzGerald, Mark J. | Hébert, Jacques | Cognet-Sicé, Josiane | Renahan, Kevin E. | Huq, Saiful | Chooniedass, Rishma | Sawyer, Scott | Pasterkamp, Hans | Becker, Allan | Smith, Steven G. | Zhang, Shiyuan | Jayasundara, Kavisha | Tacon, Claire | Simidchiev, Alex | Nadeau, Gilbert | Gunsoy, Necdet | Mullerova, Hana | Albers, Frank | Kim, Young Woong | Shannon, Casey P. | Singh, Amrit | Neighbour, Helen | Larché, Mark | Tebbutt, Scott J. | Klopp, Annika | Vehling, Lorena | Becker, Allan B. | Subbarao, Padmaja | Mandhane, Piushkumar J. | Turvey, Stuart E. | Sears, Malcolm R. | Azad, Meghan B. | Loewen, Keely | Monchka, Barret | Mahmud, Salaheddin M. | Jong, Geert ‘t | Longo, Cristina | Bartlett, Gillian | Ducharme, Francine M. | Schuster, Tibor | MacGibbon, Brenda | Barnett, Tracie | North, Michelle L. | Brook, Jeff | Lee, Elizabeth | Omana, Vanessa | Thiele, Jenny | Steacy, Lisa M. | Evans, Greg | Diamond, Miriam | Sussman, Gordon L. | Amistani, Yann | Abiteboul, Kathy | Tenn, Mark W. | Yang, ChenXi | Carlsten, Christopher | Conway, Edward M. | Mack, Douglas | Othman, Yasmin | Barber, Colin M. | Kalicinsky, Chrystyna | Burke, Andrea E. | Messieh, Mary | Nair, Parameswaran | Che, Chun T. | Douglas, Lindsay | Liem, Joel | Duan, Lucy | Miller, Charlotte | Dupuis, Pascale | Connors, Lori A. | Fein, Michael N. | Shuster, Joseph | Hadi, Hani | Polk, Brooke | Raje, Nikita | Labrosse, Roxane | Bégin, Philippe | Paradis, Louis | Roches, Anne Des | Lacombe-Barrios, Jonathan | Mishra, Sanju | Lacuesta, Gina | Chiasson, Meredith | Haroon, Babar | Robertson, Kara | Issekutz, Thomas | Leddin, Desmond | Couban, Stephen | Connors, Lori | Roos, Adrienne | Kanani, Amin | Chan, Edmond S. | Schellenberg, Robert | Rosenfield, Lana | Cvetkovic, Anna | Woodward, Kevin | Quirt, Jaclyn | Watson, Wade T. A. | Castilho, Edson | Sullivan, Jennifer A. | Temple, Beverley | Martin, Donna | Cook, Victoria E. | Mills, Christopher | Portales-Casamar, Elodie | Fu, Lisa W. | Ho, Alexander | Zaltzman, Jeffrey | Chen, Lucy | Vadas, Peter | Gabrielli, Sofianne | Clarke, Ann | Eisman, Harley | Morris, Judy | Joseph, Lawrence | LaVieille, Sebastien | Ben-Shoshan, Moshe | Graham, François | Barnes, Charles | Portnoy, Jay | Stagg, Vincent | Simons, Elinor | Lefebvre, Diana | Dai, David | Mandhane, Piushkumar | Sears, Malcolm | Tam, Herman | Simons, F. Estelle R. | Alotaibi, Dhaifallah | Dawod, Bassel | Tunis, Matthew C. | Marshall, Jean | Desjardins, Marylin | Béland, Marianne | Lejtenyi, Duncan | Drolet, Jean-Phillipe | Lemire, Martine | Tsoukas, Christos | Noya, Francisco J.D. | Alizadehfar, Reza | McCusker, Christine T. | Mazer, Bruce D. | Maestre-Batlle, Danay | Gunawan, Evelyn | Rider, Christopher F. | Bølling, Anette K. | Pena, Olga M. | Suez, Daniel | Melamed, Isaac | Hussain, Iftikhar | Stein, Mark | Gupta, Sudhir | Paris, Kenneth | Fritsch, Sandor | Bourgeois, Christelle | Leibl, Heinz | McCoy, Barbara | Noel, Martin | Yel, Leman | Scott, Ori | Reid, Brenda | Atkinson, Adelle | Kim, Vy Hong-Diep | Roifman, Chaim M. | Grunebaum, Eyal | AlSelahi, Eiman | Aleman, Fernando | Oberle, Amber | Trus, Mike | Sussman, Gordon | Kanani, Amin S. | Chambenoi, Olivier | Chiva-Razavi, Sima | Grodecki, Savannah | Joshi, Nikhil | Menikefs, Peter | Holt, David | Pun, Teresa | Tworek, Damian | Hanna, Raphael | Heroux, Delia | Rosenberg, Elli | Stiemsma, Leah | Turvey, Stuart | Denburg, Judah | Mill, Christopher | Teoh, Timothy | Zimmer, Preeti | Avinashi, Vishal | Paina, Mihaela | Darwish Hassan, Ahmed A. | Oliveria, John Paul | Olesovsky, Chris | Gauvreau, Gail | Pedder, Linda | Keith, Paul K. | Plunkett, Greg | Bolner, Michelle | Pourshahnazari, Persia | Stark, Donald | Vostretsova, Kateryna | Moses, Andrew | Wakeman, Andrew | Singer, Alexander | Gerstner, Thomas | Abrams, Elissa | Johnson, Sara F. | Woodgate, Roberta L.
PMCID: PMC5390240
6.  The impact of comorbidities on productivity loss in asthma patients 
Respiratory Research  2016;17(1):106.
Health-related productivity loss is an important, yet overlooked, component of the economic burden of disease in asthma patients of a working age. We aimed at evaluating the effect of comorbidities on productivity loss among adult asthma patients.
In a random sample of employed adults with asthma, we measured comorbidities using a validated self-administered comorbidity questionnaire (SCQ), as well as productivity loss, including absenteeism and presenteeism, using validated instruments. Productivity loss was measured in 2010 Canadian dollars ($). We used a two-part regression model to estimate the adjusted difference of productivity loss across levels of comorbidity, controlling for potential confounding variables.
284 adults with the mean age of 47.8 (SD 11.8) were included (68 % women). The mean SCQ score was 2.47 (SD 2.97, range 0–15) and the average productivity loss was $317.5 per week (SD $858.8). One-unit increase in the SCQ score was associated with 14 % (95 % CI 1.02–1.28) increase in the odds of reporting productivity loss, and 9.0 % (95 % CI 1.01–1.18) increase in productivity loss among those reported any loss of productivity. A person with a SCQ score of 15 had almost $1000 per week more productivity loss than a patient with a SCQ of zero.
Our study deepens the evidence-base on the burden of asthma, by demonstrating that comorbidities substantially decrease productivity in working asthma patients. Asthma management strategies must be cognizant of the role of comorbidities to properly incorporate the effect of comorbidity and productivity loss in estimating the benefit of disease management strategies.
PMCID: PMC5002149  PMID: 27565431
Asthma; Comorbidities; Productivity loss; Presenteeism; Absenteeism
7.  Short-term diesel exhaust inhalation in a controlled human crossover study is associated with changes in DNA methylation of circulating mononuclear cells in asthmatics 
Changes in DNA methylation have been associated with traffic-related air pollution in observational studies, but the specific mechanisms and temporal dynamics therein have not been explored in a controlled study of asthmatics. In this study, we investigate short-term effects of diesel exhaust inhalation on DNA methylation levels at CpG sites across the genome in circulating blood in asthmatics.
A double-blind crossover study of filtered air and diesel exhaust exposures was performed on sixteen non-smoking asthmatic subjects. Blood samples were collected pre-exposure, and then 6 and 30 hours post-exposure. Peripheral blood mononuclear cell DNA methylation was interrogated using the Illumina Infinium HumanMethylation450 Array. Exposure-related changes in DNA methylation were identified. In addition, CpG sites overlapping with Alu or LINE1 repetitive elements and candidate microRNA loci were also analyzed.
DNA methylation at 2827 CpG sites were affected by exposure to diesel exhaust but not filtered air; these sites enriched for genes involved in protein kinase and NFkB pathways. CpG sites with significant changes in response to diesel exhaust exposure primarily became less methylated, with a site residing within GSTP1 being among the significant hits. Diesel exhaust-associated change was also found for CpG sites overlapping with Alu and LINE1 elements as well as for a site within miR-21.
Short-term exposure to diesel exhaust resulted in DNA methylation changes at CpG sites residing in genes involved in inflammation and oxidative stress response, repetitive elements, and microRNA. This provides plausibility for the role of DNA methylation in pathways by which airborne particulate matter impacts gene expression and offers support for including DNA methylation analysis in future efforts to understand the interactions between environmental exposures and biological systems.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-014-0071-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4268899  PMID: 25487561
Particulate matter; Air pollution; Epigenetics; Interspersed repetitive sequences; microRNAs
8.  Th17/Treg ratio derived using DNA methylation analysis is associated with the late phase asthmatic response 
The imbalance between Th17 and Treg cells has been studied in various diseases including allergic asthma but their roles have not been fully understood in the development of the late phase asthmatic response.
To determine changes in Th17 and Treg cell numbers between isolated early responders (ERs) and dual responders (DRs) undergoing allergen inhalation challenge. To identify gene expression profiles associated with Th17 and Treg cells.
14 participants (8 ERs and 6 DRs) with mild allergic asthma underwent allergen inhalation challenge. Peripheral blood was collected prior to and 2 hours post allergen challenge. DNA methylation analysis was used to quantifiy the relative frequencies of Th17, Tregs, total B cells, and total T cells. Gene expression from whole blood was measured using microarrays. Technical replication of selected genes was performed using nanoString nCounter Elements.
The Th17/Treg ratio significantly increased in DRs compared to ERs post allergen challenge compared to pre-challenge. Genes significantly correlated to Th17 and Treg cell counts were inversely correlated with each other. Genes significantly correlated with Th17/Treg ratio included the cluster of genes of the leukocyte receptor complex located on chromosome 19q 13.4.
Th17/Treg imbalance post-challenge may contribute to the development of the late phase inflammatory phenotype.
PMCID: PMC4078401  PMID: 24991220
Allergen inhalation challenge; Asthma, Asthmatic response; DNA methylation; Epigenetic cell counting; Peripheral blood; Th17/Treg ratio, nCounter Elements
9.  GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study 
Environmental Health Perspectives  2014;122(4):418-424.
Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.
Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.
Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated.
Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.
Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424;
PMCID: PMC3984232  PMID: 24465030
12.  MicroRNA Expression in Response to Controlled Exposure to Diesel Exhaust: Attenuation by the Antioxidant N-Acetylcysteine in a Randomized Crossover Study 
Environmental Health Perspectives  2013;121(6):670-675.
Background: Adverse health effects associated with diesel exhaust (DE) are thought to be mediated in part by oxidative stress, but the detailed mechanisms are largely unknown. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally and may respond to exposures such as DE.
Objectives: We profiled peripheral blood cellular miRNAs in participants with mild asthma who were exposed to controlled DE with and without antioxidant supplementation.
Methods: Thirteen participants with asthma underwent controlled inhalation of filtered air and DE in a double-blinded, randomized crossover study of three conditions: a) DE plus placebo (DEP), b) filtered air plus placebo (FAP), or c) DE with N-acetylcysteine supplementation (DEN). Total cellular RNA was extracted from blood drawn before exposure and 6 hr after exposure for miRNA profiling by the NanoString nCounter assay. MiRNAs significantly associated with DEP exposure and a predicted target [nuclear factor (erythroid-derived 2)-like 2 (NRF2)] as well as antioxidant enzyme genes were assessed by reverse transcription–quantitative polymerase chain reaction (RT-qPCR) for validation, and we also assessed the ability of N-acetylcysteine supplementation to block the effect of DE on these specific miRNAs. 8-hydroxy-2´-deoxyguanosine (8-OHdG) was measured in plasma as a systemic oxidative stress marker.
Results: Expression of miR-21, miR-30e, miR-215, and miR-144 was significantly associated with DEP. The change in miR-144 was validated by RT-qPCR. NRF2 and its downstream antioxidant genes [glutamate cysteine ligase catalytic subunit (GCLC) and NAD(P)H:quinone oxidoreductase 1 (NQO1)] were negatively associated with miR-144 levels. Increases in miR-144 and miR-21 were associated with plasma 8-hydroxydeoxyguanosine 8-OHdG level and were blunted by antioxidant (i.e, DEN).
Conclusions: Systemic miRNAs with plausible biological function are altered by acute moderate-dose DE exposure. Oxidative stress appears to mediate DE-associated changes in miR-144.
PMCID: PMC3672916  PMID: 23584289
air pollution; asthma; controlled diesel exhaust exposure; hsa-miR-144; microRNA; N-acetylcysteine; NanoString nCounter assay; NRF2; oxidative stress; peripheral blood
13.  Decreased miR-192 expression in peripheral blood of asthmatic individuals undergoing an allergen inhalation challenge 
BMC Genomics  2012;13:655.
MicroRNAs are small non-coding RNAs that regulate gene expression at the post-transcriptional level. While they have been implicated in various diseases, the profile changes in allergen inhalation challenge are not clarified in human. We aimed to evaluate changes in the microRNA profiles in the peripheral blood of asthmatic subjects undergoing allergen inhalation challenge.
Seven mild asthmatic subjects participated in the allergen inhalation challenge. In addition, four healthy control subjects (HCs) were recruited. MicroRNA profiles in peripheral blood samples (pre-challenge and 2 hours post-challenge) were measured by the NanoString nCounter assay to determine changes in miRNA levels as these asthmatic subjects underwent an allergen inhalation challenge. One common miRNA, miR-192, was significantly expressed in both comparisons; HCs vs. pre-challenge and pre- vs. post-challenge, showing that miR-192 was significantly under-expressed in asthmatics compared to HCs and decreased in post-challenge at an FDR of 1%. Cell-specific statistical deconvolution attributed miR-192 expression in whole blood to PBMCs. MiR-192 was technically validated using real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showing that the level in asthmatics (pre-challenge) was significantly lower than HCs and that post-challenge was significantly lower than pre-challenge. The normalized relative miR-192 expression quantified using RT-qPCR specific to PBMCs was also validated. Ontology enrichment and canonical pathway analyses for target genes suggested several functions and pathways involved in immune response and cell cycle.
The miRNA profile in peripheral blood was altered after allergen inhalation challenge. Change in miR-192 levels may be implicated in asthma mechanisms. These results suggest that allergen inhalation challenge is a suitable method to characterize peripheral miRNA profiles and potentially elucidate the mechanism of human asthma.
PMCID: PMC3598672  PMID: 23170939
Allergen inhalation challenge; Allergy; Asthma; Blood cells; Hsa-miR-192; MicroRNAs; NanoString nCounter assay
14.  Effect of diesel exhaust inhalation on antioxidant and oxidative stress responses in adults with metabolic syndrome 
Inhalation toxicology  2009;21(13):1061-1067.
Traffic-related air pollution is associated with cardiovascular morbidity and mortality. Although the biological mechanisms are not well understood, oxidative stress may be a primary pathway. Subpopulations, such as individuals with metabolic syndrome (MeS), may be at increased risk of adverse effects associated with air pollution. Our aim was to assess the relationship between exposure to diesel exhaust (DE) and indicators of systemic antioxidant and oxidative responses in adults with MeS. We hypothesized that DE exposure would result in greater oxidative stress and antioxidant responses compared with filtered air (FA).
Ten adult subjects with MeS were exposed on separate days for two hours to FA or DE (at 200μg/m3), in a double blind, crossover experiment. Urinary 8-isoPGF2α (F2-isoprostanes), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were assessed as markers of oxidative stress at 3 hrs and 22 hrs, respectively, after exposure initiation. To assess the short-term antioxidant response we analyzed plasma ascorbic acid (AA) 90 minutes after exposure initiation. All outcomes were compared to pre-exposure levels, and mean changes were compared between FA and DE exposures.
Mean changes in urinary F2-isoprostanes (ng/mg creatinine), (-0.05 [95% CI = −0.29, 0.15]), and 8-OHdG (μg/g creatinine) (-0.09 [-0.13, 0.31]), were not statistically significant. Mean changes in plasma AA (mg/dl) were also not significant (-0.02 [-0.78, 0.04]).
In this carefully controlled experiment, we did not detect significant changes in oxidative stress or systemic antioxidant responses in subjects with MeS exposed to 200μg/m3 DE.
PMCID: PMC3075948  PMID: 19852547
Air pollution; diesel exhaust; oxidative stress; antioxidants; metabolic syndrome; controlled exposure experiment; crossover studies; vehicle emissions/toxicity; adult; biological markers; human; male; female

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