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BACKGROUND: Asthma is routinely treated with inhaled corticosteroids (ICS). Asthma patients on ICS are at increased risk of adrenal suppression, a potentially serious effect of long-term glucocorticoid exposure; however, this relationship is poorly understood. Therefore, this study aims to identify metabolite biomarkers related to adrenal suppression in asthma patients taking ICS. METHODS: A total of 571 urine metabolites from 200 children with asthma on ICS in the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) cohort were profiled. Samples were grouped by peak plasma cortisol measurement as adrenal sufficient (>350 nmol/L) or insufficient (≤350 nmol/L) (outcome). Regression and discriminant-based statistical models combined with network analyses were utilized to assess relationships between metabolites and the outcome. Finally, prioritized metabolites were validated using data from an ancillary study of the Childhood Asthma Management (CAMP) cohort with similar characteristics to PASS. RESULTS: Ninety metabolites were significantly associated with adrenal suppression, of which 57 also could discriminate adrenal status. While 26 metabolites (primarily steroids) were present at lower levels in the adrenal insufficient patients, 14 were significantly elevated in this group; the top metabolite, mannitol/sorbitol, was previously associated with asthma exacerbations. Network analyses identified unique clusters of metabolites related to steroids, fatty acid oxidation, and nucleoside metabolism, respectively. Four metabolites including urocanic acid, acetylcarnitine, uracil, and sorbitol were validated in CAMP cohort for adrenal suppression. CONCLUSIONS: Urinary metabolites differ among asthma patients on ICS, by adrenal status. While steroid metabolites were reduced in patients with poor adrenal function, our findings also implicate previously unreported metabolites involved in amino acid, lipid, and nucleoside metabolism.
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Corticoesteroides , Asma , Metabolómica , Humanos , Asma/tratamiento farmacológico , Asma/orina , Asma/sangre , Asma/diagnóstico , Niño , Masculino , Femenino , Administración por Inhalación , Metabolómica/métodos , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Biomarcadores/orina , Biomarcadores/sangre , Adolescente , Metaboloma/efectos de los fármacos , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/sangre , Insuficiencia Suprarrenal/orina , Insuficiencia Suprarrenal/etiología , Insuficiencia Suprarrenal/tratamiento farmacológico , Preescolar , Hidrocortisona/sangre , Hidrocortisona/orina , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Estudios de CohortesRESUMEN
Exposure to 1-bromopropane (1-BP) is an emerging environmental and health concern due to its increasing environmental prevalence. Although the health effects of 1-BP exposure have been under-recognized, current evidence suggests the possibility of adverse pulmonary health effects due to 1-BP exposure. However, the association between 1-BP exposure and asthma prevalence remains unclear. Thus, we aimed to examine the association between 1-BP exposure and asthma prevalence in the general population. Using nationally representative data, we explored the potential impacts of indoor air quality (IAQ)-related behavioral factors on the level of 1-BP exposure. This study included 1506 adults from the 2020-2021 Korea National Health and Nutrition Examination Survey. The prevalence of asthma was based on self-reported physician-diagnosed asthma. Urinary N-acetyl-S-(n-propyl)-L-cysteine (BPMA) levels were measured as a biomarker of 1-BP exposure, using high-performance liquid chromatography-mass spectrometry. Multiple logistic regression models were performed to investigate the associations between urinary BPMA metabolite and asthma prevalence after adjusting for potential confounders. Log-linear multiple regression models were used to examine the association between IAQ-related behavior and urinary BPMA concentration. Forty-seven individuals with asthma and 1459 without asthma were included. Individuals in the highest quartile of urinary BPMA concentration had a 2.9 times higher risk of asthma than those in the lowest quartile (odds ratio [OR]: 2.85, 95% confidence interval [CI]: 1.02-7.98). The combination of natural and mechanical ventilation was associated with a reduced urinary BPMA concentration. Our findings suggest that 1-BP exposure is associated with the prevalence of asthma in adults and revealed higher urinary levels of BPMA in our study population compared to those in other countries. Given the emerging importance of IAQ, actively managing and modifying behavioral patterns to reduce 1-BP exposure in indoor environments could substantially attenuate the risk of asthma-related to 1-BP exposure.
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Asma , Hidrocarburos Bromados , Encuestas Nutricionales , Humanos , Asma/epidemiología , Asma/orina , Asma/inducido químicamente , República de Corea/epidemiología , Femenino , Masculino , Adulto , Prevalencia , Persona de Mediana Edad , Hidrocarburos Bromados/orina , Contaminación del Aire Interior/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Adulto Joven , Contaminantes Atmosféricos/orina , Contaminantes Atmosféricos/análisis , AncianoRESUMEN
Urine metabolomics based on ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS) was utilized to investigate the metabolic regulation mechanism of Tingli Dazao Xiefei Decoction(TLDZ) in rats with allergic asthma. SD male rats were divided into a normal group, a model group, a dexamethasone group, and a TLDZ group. The allergic asthma model was established by intraperitoneal injection of ovalbumin(OVA) to induce allergy, combined with atomization excitation. Urine metabolites from all rats were collected by UHPLC-Q-TOF-MS. The metabolic profiles of rats in each group were built by principal component analysis(PCA). Besides, the differential metabolites between the model group and the TLDZ group were selected by orthogonal partial least squares discriminant analysis(OPLS-DA), t-test(P<0.05), and variable importance in the projection(VIP) values of more than 3. The differential metabolites were identified through HMDB, METLIN, and other online databa-ses. Heat maps and clustering analysis for relative quantitative information of biomarkers in each group were drawn by MeV 4.8.0 software. Finally, MetaboAnalyst, MBRole, and KEGG databases were used to enrich related metabolic pathways and construct metabolic networks. The result demonstrated that TLDZ could effectively regulate the disordered urine metabolic profiles of asthmatic rats. Combined with multivariate statistical analysis and online databases, a total of 45 differential metabolites with significant changes(P<0.05) between the model group and the TLDZ group were screened out. Metabolic pathways including histidine metabolism, tryptophan metabolism, and arginine and proline metabolism were enriched. TLDZ could improve asthma by regulating related metabolic pathways and interfering with pathological processes such as immune homeostasis airway inflammation. The study investigates the molecular mechanism of anti-asthma of TLDZ from the perspective of urine metabolomics, and combined with previous pharmacological studies, it provides a scientific basis for the clinical development and application of TLDZ in the treatment of asthma.
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Asma , Medicamentos Herbarios Chinos , Metabolómica , Ratas Sprague-Dawley , Animales , Asma/tratamiento farmacológico , Asma/orina , Asma/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Masculino , Ratas , Cromatografía Líquida de Alta Presión , Humanos , Orina/química , Espectrometría de Masas en TándemRESUMEN
INTRODUCTION: Eosinophil-derived neurotoxin (EDN) is a biomarker for eosinophilic activation. Urinary (u) EDN may allow non-invasive monitoring of asthma, but clinical recommendations are lacking. We assessed the potential of uEDN as a marker of disease activity in pediatric asthma. METHODS: We assessed urine samples of 371 children from the German ALLIANCE study cohort, from which we had: 169 preschool wheezers (<6 years), 80 asthmatics (≥6 years), and 122 healthy controls using the ImmunoCAP™ EDN Assay. Creatinine (Cr)-adjusted uEDN values were analyzed using correlations, association tests, (non) parametric statistics, multiple linear, and multivariable regression. RESULTS: uEDN/uCr values were higher in atopic versus non-atopic preschool-aged subjects (p = .035) and associated with the sum of allergen-specific IgE in younger (r = 0.24, p = .003), and older subjects (r = 0.23, p = .043). uEDN/uCr was marginally a good determinant for atopy (p = .078, for subjects aged <6 years, and p = .058 for subjects ≥6 years). Children with the T2-high phenotype had higher uEDN/uCr (p < .001) versus T2-low-irrespective of using uEDN/uCr or blood eosinophils in combination to allergen sIgE for disease phenotyping. uEDN/uCr significantly correlated with reduced lung function among asthmatics (FEV1 z-scores: r = -0.30, p = .007, and FEV1/FVC z-scores: r = -0.24, p = .038). Using multivariable modeling, uEDN/uCr was an independent determinant of FEV1 (p = .038), and to a lesser extent, FEV1/FVC (p = .080). CONCLUSIONS: uEDN/uCr may serve as a non-invasive biomarker for clinical features such as lung function in pediatric asthma. We highlight the utility of uEDN/uCr as a biomarker that can be easily assessed using widely available robust diagnostic immunoassays.
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Asma , Biomarcadores , Neurotoxina Derivada del Eosinófilo , Humanos , Asma/orina , Asma/diagnóstico , Asma/fisiopatología , Neurotoxina Derivada del Eosinófilo/orina , Masculino , Femenino , Niño , Preescolar , Biomarcadores/orina , Eosinófilos/inmunología , Inmunoglobulina E/sangre , Pulmón/fisiopatología , Pruebas de Función Respiratoria/métodos , AdolescenteRESUMEN
BACKGROUND: Adrenal steroids play important roles in early-life development. However, our understanding of the effects of perinatal adrenal steroids on the development of childhood asthma is incomplete. OBJECTIVE: To evaluate the associations between early-life adrenal steroid levels and childhood asthma. METHODS: Participants included the Infant Susceptibility to Pulmonary Infections and Asthma following Respiratory Syncytial Virus Exposure birth cohort children with untargeted urinary metabolomics data measured during early infancy (n = 264) and nasal immune mediator data measured concurrently at age 2 to 6 months (n = 76). A total of 11 adrenal steroid compounds were identified using untargeted metabolomics and 6 asthma-relevant nasal immune mediators from multiplex assays were a priori selected. Current asthma at ages 5 and 6 years was ascertained using validated questionnaires. Associations were tested using logistic and linear regression with confounders adjustment. RESULTS: Pregnenetriol disulfate (adjusted odds ratio [aOR] = 0.20, 95% CI = 0.06-0.68) and 3a,21-dihydroxy-5b-pregnane-11,20-dione-21-glucuronide (aOR = 0.34, 95% CI = 0.14-0.75) were inversely associated with childhood asthma at 5 and 6 years after multiple testing adjustment. There was a significant interaction effect of pregnanediol-3-glucuronide by biological sex assigned at birth (aOR = 0.11, 95% CI = 0.02-0.51, for those with female sex) on childhood asthma. Pregnenetriol disulfate was inversely associated with granulocyte-macrophage colony-stimulating factor (ß = -0.45, q-value = 0.05). 3a,21-dihydroxy-5b-pregnane-11,20-dione 21-glucuronide was inversely associated with interleukin [IL]-4 (ß = -0.29, q-value = 0.02), IL-5 (ß = -0.35, q-value = 0.006), IL-13 (ß = -0.26, q-value = 0.02), granulocyte-macrophage colony-stimulating factor (ß = -0.35, q-value = 0.006), and fibroblast growth factor-ß (ß = -0.24, q-value = 0.01) after multiple testing adjustment. CONCLUSION: The inverse association between adrenal steroids downstream of progesterone and 17-hydroxypregnenolone and the odds of childhood asthma and nasopharyngeal type 2 immune biomarkers suggest that increased early-life adrenal steroids may suppress type 2 inflammation and protect against the development of childhood asthma.
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Asma , Humanos , Asma/orina , Asma/epidemiología , Masculino , Femenino , Lactante , Preescolar , Niño , Corticoesteroides/orina , Corticoesteroides/uso terapéutico , Infecciones por Virus Sincitial Respiratorio/orina , Infecciones por Virus Sincitial Respiratorio/inmunología , Factores de RiesgoRESUMEN
A multimorbidity-focused approach may reflect common etiologic mechanisms and lead to better targeting of etiologic agents for broadly impactful public health interventions. Our aim was to identify clusters of chronic obesity-related, neurodevelopmental, and respiratory outcomes in children, and to examine associations between cluster membership and widely prevalent chemical exposures to demonstrate our epidemiologic approach. Early to middle childhood outcome data collected 2011-2022 for 1092 children were harmonized across the ECHO-PATHWAYS consortium of 3 prospective pregnancy cohorts in six U.S. cities. 15 outcomes included age 4-9 BMI, cognitive and behavioral assessment scores, speech problems, and learning disabilities, asthma, wheeze, and rhinitis. To form generalizable clusters across study sites, we performed k-means clustering on scaled residuals of each variable regressed on study site. Outcomes and demographic variables were summarized between resulting clusters. Logistic weighted quantile sum regressions with permutation test p-values associated odds of cluster membership with a mixture of 15 prenatal urinary phthalate metabolites in full-sample and sex-stratified models. Three clusters emerged, including a healthier Cluster 1 (n = 734) with low morbidity across outcomes; Cluster 2 (n = 192) with low IQ and higher levels of all outcomes, especially 0.4-1.8-standard deviation higher mean neurobehavioral outcomes; and Cluster 3 (n = 179) with the highest asthma (92 %), wheeze (53 %), and rhinitis (57 %) frequencies. We observed a significant positive, male-specific stratified association (odds ratio = 1.6; p = 0.01) between a phthalate mixture with high weights for MEP and MHPP and odds of membership in Cluster 3 versus Cluster 1. These results identified subpopulations of children with co-occurring elevated levels of BMI, neurodevelopmental, and respiratory outcomes that may reflect shared etiologic pathways. The observed association between phthalates and respiratory outcome cluster membership could inform policy efforts towards children with respiratory disease. Similar cluster-based epidemiology may identify environmental factors that impact multi-outcome prevalence and efficiently direct public policy efforts.
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Asma , Contaminantes Ambientales , Ácidos Ftálicos , Rinitis , Femenino , Embarazo , Humanos , Niño , Masculino , Preescolar , Estudios Prospectivos , Ácidos Ftálicos/efectos adversos , Ácidos Ftálicos/orina , Asma/epidemiología , Asma/orina , Ruidos Respiratorios/etiología , Evaluación de Resultado en la Atención de Salud , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/efectos adversos , Contaminantes Ambientales/orinaRESUMEN
BACKGROUND: We investigated the correlation between urine VOC metabolites and airway function in children exposed to anthropogenic volatile organic compounds (VOCs), notable pollutants impacting respiratory health. METHODS: Out of 157 respondents, 141 completed skin prick tests, spirometry, IOS, and provided urine samples following the International Study of Asthma and Allergies in Childhood (ISAAC)-related questions. Allergic sensitization was assessed through skin prick tests, and airway functions were evaluated using spirometry and impulse oscillometry (IOS). Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) was recorded and FEV1/FVC ratio was calculated. Airway mechanics parameters including respiratory resistance at 5 Hz (Rrs5) mean respiratory resistance between 5 Hz and 20 Hz (Rrs5-20), were also recorded. Urine concentrations of metabolites of benzene, ethylbenzene, toluene, xylene, styrene, formaldehyde, carbon-disulfide were analyzed by gas chromatography/tandem mass spectroscopy. RESULTS: The median age at study participation was 7.1 (SD 0.3) years. Muconic acid (benzene metabolites) and o-methyl-hippuric acid (xylene metabolites) above medians were associated with a significant increase in Rrs5 (muconic acid: aß = 0.150, p = .002; o-methyl-hippuric acid: aß = 0.143, p = .023) and a decrease in FEV1/FVC (o-methyl-hippuric acid: aß = 0.054, p = .028) compared to those below median. No associations were observed for Rrs5-20 and FEV1 between the groups categorized as above and below the median (all parameter p values > .05). CONCLUSIONS: Elevated levels of benzene and xylene metabolites were associated with a significant increase in Rrs5 and a decrease in FEV1/FVC, related to increased resistance and restrictive lung conditions compared to individuals with concentrations below the median.
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Compuestos Orgánicos Volátiles , Humanos , Niño , Compuestos Orgánicos Volátiles/orina , Masculino , Femenino , Capacidad Vital , Espirometría , Volumen Espiratorio Forzado , Pruebas Cutáneas , Ácido Sórbico/análogos & derivados , Ácido Sórbico/análisis , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Pruebas de Función Respiratoria , Xilenos/orina , Benceno/análisis , Resistencia de las Vías Respiratorias , Derivados del Benceno/orina , Contaminantes Atmosféricos/orina , Contaminantes Atmosféricos/análisis , Contaminantes Atmosféricos/efectos adversos , Asma/orina , Asma/fisiopatología , Hipuratos/orina , Oscilometría , PulmónRESUMEN
OBJECTIVE: To provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated respiratory disease (AERD), and asthma. DATA SOURCES: Ovid MEDLINE(R), Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. REVIEW METHODS: A state-of-the-art review was performed investigating the role of uLTE4 as a diagnostic biomarker, predictor of disease severity, and potential marker of selected therapeutic efficacy. CONCLUSIONS: uLTE4 has been shown to be a reliable and clinically relevant biomarker for CRS, AERD, and asthma. uLTE4 is helpful in ongoing efforts to better endotype patients with CRS and to predict disease severity. IMPLICATIONS FOR PRACTICE: Aside from being a diagnostic biomarker, uLTE4 is also able to differentiate aspirin-tolerant patients from patients with AERD and has been associated with objective disease severity in patients with CRS with nasal polyposis. uLTE4 levels have also been shown to predict response to medical therapy, particularly leukotriene-modifying agents.
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Asma/diagnóstico , Biomarcadores/orina , Leucotrieno E4/orina , Rinitis/diagnóstico , Sinusitis/diagnóstico , Asma/orina , Asma Inducida por Aspirina/diagnóstico , Asma Inducida por Aspirina/orina , Enfermedad Crónica , Humanos , Rinitis/orina , Sinusitis/orinaRESUMEN
BACKGROUND: Environmental tobacco smoke exposure due to parents is a modifiable risk factor for childhood asthma, but many studies have evaluated parental smoking using self-reported data. Therefore, we aimed to analyze the relationship between parental cotinine-verified smoking status and asthma in their children. METHODS: This population-based cross-sectional study used data from the Korean National Health and Nutrition Examination Survey from 2014 to 2017. Participants aged 0 to 18 years with complete self-reported physician-diagnosed childhood asthma and measurement of their parental urinary cotinine levels were included. Parental urinary cotinine-verified smoking status was defined using both urinary cotinine levels and self-report, as active, passive, and non-smoker. Sample weights were applied to all statistical analyses because of a complex, multistage and clustered survey design. Logistic regression model was used to analyze the relationship between childhood asthma and parental smoking. RESULTS: A total of 5,264 subjects aged < 19 years were included. The prevalence of asthma was 3.4%. The proportions of paternal and maternal urinary cotinine-verified active smokers during the study period were 50.4% and 16.9%, respectively. When parental urinary cotinine level increased, the proportion of parental low household income was increased (P < 0.001). There was no significant association between the parental urinary cotinine-verified smoking group and childhood asthma group. However, the adjusted odds ratios of childhood asthma in the middle and highest tertile of paternal urinary cotinine levels compared with those in lowest tertile were 1.95 (95% confidence interval [CI], 0.98-3.89) and 2.34 (95% CI, 1.21-4.54), respectively. CONCLUSION: There seems to be a dose-related association between paternal urinary cotinine levels and the risk of childhood asthma. Because of the high rate of paternal smoking, further studies are needed to develop a targeted strategy to reduce parental smoking for childhood asthma.
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Asma/etiología , Cotinina/orina , Exposición a Riesgos Ambientales/efectos adversos , Padres , Fumar/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Adulto , Consumo de Bebidas Alcohólicas/epidemiología , Asma/epidemiología , Asma/orina , Niño , Estudios Transversales , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , República de Corea/epidemiología , Factores de Riesgo , Autoinforme , Fumar/epidemiología , Encuestas y CuestionariosRESUMEN
BACKGROUND: Many phenols and parabens are applied in cosmetics, pharmaceuticals and food, to prevent growth of bacteria and fungi. Whether these chemicals affect inflammatory diseases like allergies and overweight is largely unexplored. We aimed to assess the associations of use of personal care products with urine biomarkers levels of phenols and paraben exposure, and whether urine levels (reflecting body burden of this chemical exposures) are associated with eczema, rhinitis, asthma, specific IgE and body mass index. METHODS: Demographics, clinical variables, and self-report of personal care products use along with urine samples were collected concurrently from 496 adults (48% females, median age: 28 years) and 90 adolescents (10-17 years of age) from the RHINESSA study in Bergen, Norway. Urine biomarkers of triclosan (TCS), triclocarban (TCC), parabens and benzophenone-3, bisphenols and dichlorophenols (DCP) were quantified by mass spectrometry. RESULTS: Detection of the urine biomarkers varied according to chemical type and demographics. TCC was detected in 5% of adults and in 45% of adolescents, while propyl (PPB) and methyl (MPB) parabens were detected in 95% of adults and in 94% (PPB) and 99% (MPB) of adolescents. Women had higher median urine concentrations of phenolic chemicals and reported a higher frequency of use of personal care products than men. Urine concentration of MPB increased in a dose-dependent manner with increased frequency of use of several cosmetic products. Overall, urinary biomarker levels of parabens were lower in those with current eczema. The biomarker concentrations of bisphenol S was higher in participants with positive specific IgE and females with current asthma, but did not differ by eczema or rhinitis status. MPB, ethylparaben (EPB), 2,4-DCP and TCS were inversely related to BMI in adults; interaction by gender were not significant. CONCLUSIONS: Reported frequency of use of personal care products correlated very well with urine biomarker levels of paraben and phenols. Several chemicals were inversley related to BMI, and lower levels of parabens was observed for participants with current eczema. There is a need for further studies of health effects of chemicals from personal care products, in particular in longitudinally designed studies.
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Asma/orina , Índice de Masa Corporal , Carbanilidas/orina , Eccema/orina , Contaminantes Ambientales/orina , Parabenos/análisis , Fenoles/orina , Rinitis/orina , Adolescente , Adulto , Asma/epidemiología , Monitoreo Biológico , Niño , Cosméticos , Eccema/epidemiología , Femenino , Humanos , Inmunoglobulina E/sangre , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Rinitis/epidemiología , Adulto JovenRESUMEN
Asthma is the most common respiratory disease. It has multiple phenotypes thatcan be partially differentiated by measuring the disease's specific characteristics-biomarkers. The pathogenetic mechanisms are complex, and it is still a challenge to choose suitable biomarkers to adequately stratify patients, which became especially important with the introduction of biologicals in asthma treatment. Usage of biomarkers and an understanding of the underlying pathobiological mechanisms lead to the definition of endotypes. Asthma can be broadly divided into two endotypes, T2-high and T2-low. The right combination of various biomarkers in different phenotypes is under investigation, hoping to help researchers and clinicians in better disease evaluation since theindividual approach and personalized medicine are imperative. Multiple biomarkers are superior to a single biomarker.
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Asma/sangre , Asma/metabolismo , Asma/patología , Asma/orina , Biomarcadores/sangre , Biomarcadores/metabolismo , Biomarcadores/orina , Humanos , Fenotipo , Esputo/metabolismoRESUMEN
BACKGROUND: Asthma represents a syndrome for which our understanding of the molecular processes underlying discrete sub-diseases (i.e., endotypes), beyond atopic asthma, is limited. The public health needs to characterize etiology-associated endotype risks is becoming urgent. In particular, the roles of polyaromatic hydrocarbon (PAH), globally distributed combustion by-products, toward the two known endotypes - T helper 2 cell high (Th2) or T helper 2 cell low (non-Th2) - warrants clarification. OBJECTIVES: To explain ambient B[a]P association with non-atopic asthma (i.e., a proxy of non-Th2 endotype) is markedly different from that with atopic asthma (i.e., a proxy for Th2-high endotype). METHODS: In a case-control study, we compare the non-atopic as well as atopic asthmatic boys and girls against their respective controls in terms of the ambient Benzo[a]pyrene concentration nearest to their home, plasma 15-Ft2-isoprostane (15-Ft2-isoP), urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and lung function deficit. We repeated the analysis for i) dichotomous asthma outcome and ii) multinomial asthma-overweight/obese (OV/OB) combined outcomes. RESULTS: The non-atopic asthma cases are associated with a significantly higher median B[a]P (11.16 ng/m3) compared to that in the non-atopic controls (3.83 ng/m3; P-value < 0.001). In asthma-OV/OB stratified analysis, the non-atopic girls with lean and OV/OB asthma are associated with a step-wisely elevated B[a]P (median,11.16 and 18.00 ng/m3, respectively), compared to the non-atopic lean control girls (median, 4.28 ng/m3, P-value < 0.001). In contrast, atopic asthmatic children (2.73 ng/m3) are not associated with a significantly elevated median B[a]P, compared to the atopic control children (2.60 ng/m3; P-value > 0.05). Based on the logistic regression model, on ln-unit increate in B[a]P is associated with 4.7-times greater odds (95% CI, 1.9-11.5, P = 0.001) of asthma among the non-atopic boys. The same unit increase in B[a]P is associated with 44.8-times greater odds (95% CI, 4.7-428.2, P = 0.001) among the non-atopic girls after adjusting for urinary Cotinine, lung function deficit, 15-Ft2-isoP, and 8-oxodG. CONCLUSIONS: Ambient B[a]P is robustly associated with non-atopic asthma, while it has no clear associations with atopic asthma among lean children. Furthermore, lung function deficit, 15-Ft2-isoP, and 8-oxodG are associated with profound alteration of B[a]P-asthma associations among the non-atopic children.
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8-Hidroxi-2'-Desoxicoguanosina/orina , Contaminantes Atmosféricos/análisis , Asma/epidemiología , Benzo(a)pireno/análisis , Dinoprost/análogos & derivados , Adolescente , Asma/sangre , Asma/fisiopatología , Asma/orina , Estudios de Casos y Controles , Niño , Preescolar , Cotinina/orina , República Checa/epidemiología , Dinoprost/sangre , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Lactante , Pulmón/fisiopatología , Masculino , FenotipoRESUMEN
Volatile organic compounds (VOCs) are important and ubiquitous air pollutants, which may lead to a significant increase in the prevalence of respiratory diseases. To investigate the relationships between VOCs exposure and childhood asthma, 252 asthmatic children and 69 healthy children were recruited. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG, a biomarker of oxidative DNA damage), trans-3'-hydroxycotinine (OH-Cot, a biomarker of passive smoking) and 27 VOC metabolites were simultaneously determined by an ultra-high-performance liquid chromatography-tandem mass spectrometer. Results showed that levels of 8-OHdG and most VOC metabolites in asthmatic children were significantly higher than those in healthy children. More than half of the VOC metabolites were significantly and positively associated with OH-Cot with maximal ß coefficient of 0.169, suggesting that second-hand smoking is one important source of VOCs exposure for children in Guangzhou. Significant dose-response relationships between most VOC metabolites and 8-OHdG were observed. Each unit increase in ln-transformed VOC metabolite levels was significantly associated with 5.5-32% increase in ln-transformed 8-OHdG level. Moreover, each unit increase in ln-transformed 8-OHdG level was associated with an 896% increased odd ratios (OR) of asthma in children (OR = 9.96, 95% confidence intervals (CI): 4.75, 20.9), indicating that oxidative stress induced by VOCs exposure may have a significant impact on childhood asthma. Urinary 3-&4-Methylhippuric acid (3-&4-MHA, OR: 5.78, 95% CI: 3.50, 9.54), rac 2-Aminothiazoline-4-carboxylic acid (ATCA, OR: 2.90, 95% CI: 1.69, 4.99) and N-Acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA, OR: 2.76, 95% CI: 1.73, 4.43) which may derive from m/p-xylene, cyanide and 1,3-butadiene exposure, respectively, could significantly and maximally increase the odds of asthma. Interestingly, they also had the strongest associations with 8-OHdG among all investigated VOC metabolites. Moreover, DHBMA strongly correlated with most VOC metabolites. Hence, DHBMA is a suitable biomarker to indicate not only VOCs exposure profile, but also the DNA damage-mediated asthma induced by VOCs.
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Asma/orina , Contaminantes Ambientales/orina , Estrés Oxidativo , Contaminación por Humo de Tabaco/efectos adversos , Compuestos Orgánicos Volátiles/orina , 8-Hidroxi-2'-Desoxicoguanosina/orina , Asma/epidemiología , Monitoreo Biológico , Biomarcadores/orina , Niño , China/epidemiología , Cotinina/análogos & derivados , Cotinina/orina , Contaminantes Ambientales/metabolismo , Femenino , Humanos , Masculino , Compuestos Orgánicos Volátiles/metabolismoRESUMEN
Results of this paper provide evidence that chronic long-term exposure to organophosphorus insecticides poses a significantly higher health risk for US women than for men, based on dialkylphosphate biomarker data from NHANES cycles 2003-2012. The risk of cardiovascular disease for female non-smokers aged 60-85 years in the highest dimethylthiophosphate (DMTP) urinary concentration quartile is 3.0 (odds ratio, ODâ¯=â¯3.0, 95%CI 1.4-6.4) times higher than that in the lowest quartile. Women with higher urinary DMTP concentrations also have significantly higher risk of asthma at the ages 6-39 years and an apparently higher risk of chronic bronchitis at the ages 60-85. Overall cancer risk is significantly higher for female non-smokers aged 60-85 years in the higher urinary DMTP quartiles (ODâ¯=â¯2.7, 95% CI 1.3-5.9). Increasing risks of breast cancer for female smokers and prostate cancer for male smokers aged 60-85 years with higher exposure to organophosphorus insecticides in the US are also significant.
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Asma/epidemiología , Enfermedades Cardiovasculares/epidemiología , Insecticidas/orina , Neoplasias/epidemiología , Compuestos Organofosforados/orina , Adulto , Anciano , Anciano de 80 o más Años , Asma/orina , Monitoreo Biológico , Enfermedades Cardiovasculares/orina , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/orina , Riesgo , Caracteres Sexuales , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The incidence of obesity-related asthma has shown a remarkable increase. OBJECTIVES: We aimed to explore the role of heat shock protein 72 (Hsp72) and receptor for advanced glycation end products (RAGE) axis with its downstream signaling in the pathogenesis of obesity-related asthma. METHODS: We enrolled a total of 55 subjects and divided them into three groups. Groups I and II included healthy, normal weight (n = 15) and obese (n = 15) subjects, respectively. Twenty-five obese asthmatics (group III) were subdivided into group IIIa (10 patients with mild to moderate asthma) and group IIIb (15 patients with severe asthma). High mobility group box 1 (HMGB1), interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), and urinary Hsp72 were immunoassayed. Hydrogen peroxide (H2O2) and free fatty acids (FFAs) levels were photometrically measured. RAGE mRNA expression was relatively quantified by real-time PCR. RESULTS: We found significant elevations of serum HMGB1, IL-8, MCP1, ERK1/2, FFAs, and H2O2 levels as well as urinary Hsp72 levels in obese subjects compared to healthy control. These were more evident in patients with severe asthma (group IIIb). Multivariate regression analysis identified Hsp72 and ERK1/2 as independent predictors of bronchial asthma severity. Receiver operating characteristic (ROC) curve analysis revealed that areas under the curve (AUC) for Hsp72 and ERK1/2 were 0.991 and 0.981, respectively, which denotes a strong predictive value for identifying the severity of bronchial asthma in obese patients. CONCLUSION: The current study highlights the role of Hsp72 and HMGB1/RAGE/ERK1/2 signaling cascade in the pathogenesis of bronchial asthma and its link to obesity, which could be reflected on monitoring, severity grading, and management of this disease.
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Antígenos de Neoplasias/sangre , Asma/sangre , Proteína HMGB1/sangre , Proteínas de Choque Térmico/sangre , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas Activadas por Mitógenos/sangre , Chaperonas Moleculares/sangre , Obesidad/sangre , Adulto , Asma/inmunología , Asma/orina , Estudios de Casos y Controles , Quimiocina CCL2/sangre , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Femenino , Proteína HMGB1/orina , Proteínas de Choque Térmico/orina , Humanos , Peróxido de Hidrógeno/sangre , Peróxido de Hidrógeno/metabolismo , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/orina , Obesidad/inmunología , Obesidad/orina , Receptor Cross-TalkRESUMEN
Epidemiological studies have reported the relationship between bisphenol A (BPA) exposure and increased prevalence of asthma, but the mechanisms remain unclear. Here, we investigated whether BPA exposure and DNA methylation related to asthma in children. We collected urinary and blood samples from 228 children (Childhood Environment and Allergic Diseases Study cohort) aged 3 years. Thirty-three candidate genes potentially interacting with BPA exposure were selected from a toxicogenomics database. DNA methylation was measured in 22 blood samples with top-high and bottom-low exposures of BPA. Candidate genes with differential methylation levels were validated by qPCR and promoter associated CpG islands have been investigated. Correlations between the methylation percentage and BPA exposure and asthma were analyzed. According to our findings, MAPK1 showed differential methylation and was further investigated in 228 children. Adjusting for confounders, urinary BPA glucuronide (BPAG) level inversely correlated with MAPK1 promoter methylation (ß = -0.539, p = 0.010). For the logistic regression analysis, MAPK1 methylation status was dichotomized into higher methylated and lower methylated groups with cut off continuous variable of median of promoter methylation percentage (50%) while performing the analysis. MAPK1 methylation was lower in children with asthma than in children without asthma (mean ± SD; 69.82 ± 5.88% vs. 79.82 ± 5.56%) (p = 0.001). Mediation analysis suggested that MAPK1 methylation acts as a mediation variable between BPA exposure and asthma. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation. The mechanism of BPA exposure on childhood asthma might, therefore, be through the alteration of MAPK1 methylation.
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Asma , Compuestos de Bencidrilo , Metilación de ADN , Fenoles , Asma/sangre , Asma/epidemiología , Asma/orina , Compuestos de Bencidrilo/toxicidad , Compuestos de Bencidrilo/orina , Preescolar , Estudios de Cohortes , Islas de CpG/genética , Femenino , Glucurónidos/orina , Humanos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Fenoles/toxicidad , Fenoles/orina , Regiones Promotoras Genéticas/genéticaRESUMEN
Objectives: We explored the short-term impact of pesticide exposure on asthma exacerbation among children with asthma in an agricultural community.Methods: We obtained repeated urine samples from a subset of 16 school-age children with asthma (n = 139 samples) as part of the Aggravating Factors of Asthma in a Rural Environment (AFARE) study cohort. Biomarkers of organophosphate (OP) pesticide exposure (dialkylphosphates (DAPs)), and asthma exacerbation (leukotriene E4 (uLTE4)) were assessed in urine samples. We used generalized estimating equations to examine the association of summed measures of creatinine-adjusted DAPs (total dimethyl alkylphosphate (EDM), total diethyl alkylphosphate (EDE), and total dialkylphosphate pesticides (EDAP)) and uLTE4 concentration, adjusting for multiple confounders, yielding beta-coefficients with 95% CIs.Results: A total of 139 observations were obtained from the 16 children over the study period, the total number of samples per subject ranged from 1 to 12 (median: 10.5). The geometric mean (GM) of creatinine-adjusted EDE, EDM, and EDAP in this population were 81.0, 71.8 and 168.0 nmol/g, respectively. Increase in uLTE4 levels was consistently associated with increased exposures to DAPs (interquartile range in µg/g): ßEDE: 8.7 (95%CI: 2.8, 14.6); ßEDM: 1.1 (0.5, 1.7); ßEDAP: 4.1 (0.7, 7.5).Conclusion: This study suggests that short-term OP exposure is associated with a higher risk of asthma morbidity, as indicated by increased uLTE4 levels in this cohort of children with asthma in an agricultural community. Additional studies are required to confirm these adverse effects, and explore the mechanisms underlying this relationship.
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Asma/orina , Leucotrieno E4/orina , Compuestos Organofosforados/orina , Adolescente , Agricultura , Asma/metabolismo , Biomarcadores , Niño , Estudios de Cohortes , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Masculino , Plaguicidas/orina , Población Rural , WashingtónRESUMEN
OBJECTIVE: While urinary leukotriene E4 (uLTE4) is a validated biomarker for the cysteinyl leukotriene pathway, which is central to the pathophysiology of asthma, atopy, and chronic rhinosinusitis (CRS), the contributions of comorbid asthma and atopy to uLTE4 levels in various CRS subtypes have not been previously characterized. We sought to (1) identify reference values for uLTE4 in subjects with and without CRS and (2) determine how the presence of comorbid atopy and asthma affects uLTE4 levels in CRS. SETTING: Tertiary referral medical center. SUBJECTS AND METHODS: A prospective case-control study was conducted to compare uLTE4 levels between patients with CRS and healthy controls. Urinary LTE4 levels were measured by enzyme immunoassay and were adjusted for urinary creatinine concentrations (pg/mg Cr). Patients with CRS were stratified by the clinical comorbidities to determine normative uLTE4 values for patients with CRS with and without comorbid asthma or atopy. RESULTS: A total of 153 patients (mean age, 47.3; 47.1% female) were included in the study. Patients with CRS demonstrated significantly higher concentrations of uLTE4 than healthy controls (1652 vs 1065 pg/mg Cr, P = .032). Within the group of patients with CRS, comorbid asthma also individually correlated with elevated uLTE4 levels (1597 pg/mg Cr, P = .0098). Patients with CRS who did not have comorbid allergy and asthma, in contrast, did not have statistically higher uLTE4 levels than healthy controls (1142 pg/mg Cr, P = .61). CONCLUSION: Urinary LTE4 serves as a noninvasive measure of the inflammatory state in CRS. Comorbid asthma and atopy contribute to elevated uLTE4 levels in CRS.
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Asma/orina , Leucotrieno E4/orina , Rinitis/complicaciones , Rinitis/orina , Sinusitis/complicaciones , Sinusitis/orina , Adulto , Asma/complicaciones , Biomarcadores/orina , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Exercise-induced bronchoconstriction (EIB) reflects poor asthma control. Assessing noninvasive biomarkers associated with EIB could help to monitor patients in the pediatric age. AIMS: To test exhaled and urinary biomarkers for assessing EIB in atopic asthmatic children. METHODS: In 45 atopic patients (11.1 ± 1.8 years, 25 males) we measured the fractional exhaled nitric oxide (FENO ), its alveolar (CaNO), and bronchial (J'awNO) components corrected for the trumpet shape of the airways and axial NO diffusion (TMAD), concentrations of urinary adenosine and 8-hydroxy-2'-deoxyguanosine (8-OxodG), blood eosinophils count, total immunoglobulin E , skin prick tests, and baseline spirometry before a treadmill exercise challenge. Forty healthy control subjects participated solely to baseline measurements. RESULTS: Patients yielded higher FENO and urinary adenosine concentrations than healthy controls. After the challenge, 18 patients (40%) had EIB; these patients had higher levels of CaNO, CaNO TMAD, and urinary adenosine than patients without EIB. Baseline spirometry, FE NO , JawNO, JawNO TMAD, urinary 8-OxodG, allergy, and blood eosinophil counts were found similar in both groups. In multiple linear regression, the fall in FEV 1 was explained by CaNO TMAD, urinary adenosine and blood eosinophil count, whereas the fall in FEF 25-75 was explained by CaNO TMAD and blood eosinophil count. Both CaNO TMAD ≥10.5 ppb and urinary adenosine ≥406 nmol/mmol Cr predicted a fall in FEV 1 ≥10%, while only CaNO TMAD ≥10.5 ppb predicted a fall in FEF 25-75 ≥26%. CONCLUSION: Concentrations of peripheral airway NO are complementary with urinary adenosine for assessing EIB and promising tools of asthma control in pediatric patients with the atopic phenotype.
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Adenosina/orina , Asma/fisiopatología , Biomarcadores/análisis , Óxido Nítrico/análisis , Asma/inmunología , Asma/orina , Asma Inducida por Ejercicio/orina , Biomarcadores/orina , Pruebas de Provocación Bronquial , Broncoconstricción , Niño , Desoxiadenosinas/orina , Eosinófilos , Prueba de Esfuerzo , Espiración , Femenino , Humanos , Hipersensibilidad Inmediata , Inmunoglobulina E/análisis , Recuento de Leucocitos , Masculino , Pruebas Cutáneas , EspirometríaRESUMEN
BACKGROUND: The associations between excessive iodine intake and allergic diseases have not been evaluated. PURPOSE: We aimed to investigate the associations of allergic diseases with urinary iodine concentration (UIC). STUDY DESIGN: A nation-wide population-based survey conducted by the the Korean Centers for Disease Control and Prevention METHODS: In total, 5598 participants older than 19 years who participated in the Korean National Health and Nutrition Examination Survey 2013-2015 were enrolled for analysis. Multiple logistic regression analysis was used to determine the odds ratios for allergic diseases according to UIC. RESULTS: Allergic diseases were associated with the highest UIC quartile. Compared with subjects in lower UIC quartiles, subjects in the highest UIC quartile were at greater risk for atopic dermatitis (OR = 1.471, 95% CI, 1.028-2.107) and allergic rhinitis (ORâ¯=â¯1.362, 95% CI, 1.129-1.644) after adjustment for age and sex. CONCLUSION: This study revealed that the highest UIC quartile is associated with allergic diseases. Further laboratory and clinical studies are needed to evaluate the associations between excessive iodine intake and allergic diseases.