Significant strides in the understanding of the role of epigenetic regulation in asthma and allergy using both epidemiological approaches as well as experimental ones have been made. This review focuses on new research within the last two years. These include advances in determining how environmental agents implicated in airway disease can induce epigenetic changes, how epigenetic regulation can influence T helper cell (Th) differentiation and T regulatory (Treg) cell production, and new discoveries of epigenetic regulation associated with clinical outcomes.
Exposure to naphthalene, an IARC-classified possible carcinogen and polycyclic aromatic hydrocarbon (PAH), is widespread, though resulting health effects are poorly understood. Metabolites of naphthalene, 1- and 2-naphthol, are measurable in urine and are biomarkers of personal exposure. Chromosomal aberrations (CAs), including translocations, are established markers of cancer risk and a bio-dosimeter of clastogenic exposures. Although prenatal (maternal) PAH exposure predicts CAs in cord blood, few studies have examined CAs in school-age children and none has examined their association with metabolites of specific PAHs.
Using Whole Chromosome Paint Fluorescent in Situ Hybridization, we documented CAs including translocations, in 113 five year old urban minority children and examined their association with concurrent concentrations of PAH metabolites measured in urine.
We report that in lymphocytes, the occurrence and frequency of CAs including translocations are associated with levels of urinary 1- and 2-naphthol. When doubling the levels of urinary naphthols, gender-adjusted Odds Ratio (OR) for CAs are 1.63 (95%CI: 1.21, 2.19) and 1.44 (95%CI: 1.02, 2.04) for 1-and 2-naphthol respectively; and for translocations: OR=1.55 (95%CI: 1.11-2.17) and 1.92 (95%CI: 1.20-3.08) for 1- and 2-naphthol respectively.
Our results demonstrate that markers of exposure to naphthalene in children are associated with translocations in a dose related manner, and that naphthalene may be a clastogen.
Indoor exposure to elevated levels of naphthalene is prevalent in large regions of the world. This study is the first to present an association between a marker of naphthalene exposure and a pre-carcinogenic effect in humans.
Naphthalene; Chromosomal aberrations; Polycyclic aromatic hydrocarbons; Cohort study; Postnatal
Differential exposure to combustion by-products and allergens may partially explain the marked disparity in asthma prevalence (3%–18%) among New York City neighborhoods. Subclinical changes in airway inflammation can be measured by fractional exhaled nitric oxide (FeNO). FeNO could be used to test independent effects of these environmental exposures on airway inflammation. Seven and eight year-old children from neighborhoods with lower (range 3–9%, n=119) and higher (range 11–18%, n=121) asthma prevalence participated in an asthma case-control study. During home visits, FeNO was measured, and samples of bed dust (allergens) and air (black carbon) were collected. Neighborhood built-environment characteristics were assessed for the 500m surrounding participants’ homes. Airborne black carbon concentrations in homes correlated with neighborhood asthma prevalence (P<0.001) and neighborhood densities of truck routes (P<0.001) and buildings burning residual oil (P<0.001). FeNO concentrations were higher among asthmatics with compared to asthmatics without frequent wheeze (≥4 times/year) (P=0.002). FeNO concentrations correlated with domestic black carbon among children without seroatopy (P=0.012) and with dust mite allergen among children with seroatopy (P=0.020). The association between airborne black carbon in homes and both neighborhood asthma prevalence and FeNO suggest that further public health interventions on truck emissions standards and residual oil use are warranted.
Asthma; air pollution; airway inflammation; FeNO; residual oil
Environmental epigenetic regulation in asthma and allergic disease is an exciting area that has gained a great deal of scientific momentum in recent years. Environmental exposures, including prenatal maternal smoking, have been associated with asthma-related outcomes that may be explained by epigenetic regulation. In addition, several known allergy and asthma genes have been found to be susceptible to epigenetic regulation. We review the latest experimental and translational studies that have been published this past year in several areas, including 1) characterization of environmental asthma triggers that induce epigenetic changes, 2) characterization of allergic immune and regulatory pathways important to asthma that undergo epigenetic regulation, 3) evidence of active epigenetic regulation in asthma experimental models and the production of asthma biomarkers, 4) evidence of transmission of an asthma-related phenotype across multiple generations, and 5) “pharmaco-epigenetics.” The field has certainly advanced significantly in the past year.
Epigenetics; Asthma; Allergy; Environment; DNA methylation; Histone modification; microRNA; T-helper cell; Regulatory T cell; Transgenerational; Pharmaco-epigenetics
Purpose of review
Current levels of air pollution are consistently associated with asthma development and morbidity among children, suggesting that current regulatory policies may be insufficient. This review will describe recent studies that have examined specific emission sources or components of pollutants that may be associated with pediatric asthma and identify subpopulations that may be particularly susceptible to the effects of air pollution exposure.
Important advances include new characterizations of the effects of traffic-related air pollution in urban areas. They also include the application of novel exposure and outcome measures such as pollution estimates derived from land use regression modeling and biological markers of airway inflammation. Additionally, studies have identified host susceptibility characteristics that may modify responses to air pollution exposure, including polymorphisms in oxidative stress genes and epigenetic alterations.
Identifying specific sources and toxic constituents of air pollution and accurately assessing air pollutant-related asthma outcomes are needed to better direct control strategies. Further research is needed to identify additional host factors that confer increased susceptibility to air pollution exposure. Future therapy to reduce the adverse effects of air pollution on respiratory disease will likely depend on targeting susceptible populations for intervention.
air pollution; airway inflammation; asthma; oxidative stress; traffic
Background: Urban landscape elements, particularly trees, have the potential to affect airflow, air quality, and production of aeroallergens. Several large-scale urban tree planting projects have sought to promote respiratory health, yet evidence linking tree cover to human health is limited.
Objectives: We sought to investigate the association of tree canopy cover with subsequent development of childhood asthma, wheeze, rhinitis, and allergic sensitization.
Methods: Birth cohort study data were linked to detailed geographic information systems data characterizing 2001 tree canopy coverage based on LiDAR (light detection and ranging) and multispectral imagery within 0.25 km of the prenatal address. A total of 549 Dominican or African-American children born in 1998–2006 had outcome data assessed by validated questionnaire or based on IgE antibody response to specific allergens, including a tree pollen mix.
Results: Tree canopy coverage did not significantly predict outcomes at 5 years of age, but was positively associated with asthma and allergic sensitization at 7 years. Adjusted risk ratios (RRs) per standard deviation of tree canopy coverage were 1.17 for asthma (95% CI: 1.02, 1.33), 1.20 for any specific allergic sensitization (95% CI: 1.05, 1.37), and 1.43 for tree pollen allergic sensitization (95% CI: 1.19, 1.72).
Conclusions: Results did not support the hypothesized protective association of urban tree canopy coverage with asthma or allergy-related outcomes. Tree canopy cover near the prenatal address was associated with higher prevalence of allergic sensitization to tree pollen. Information was not available on sensitization to specific tree species or individual pollen exposures, and results may not be generalizable to other populations or geographic areas.
aeroallergen; allergic sensitivity; asthma; built environment; childhood disease; environmental agents; epidemiology; pollen; urban life
Recent studies suggest that epigenetic regulation (heritable changes in gene expression that occur in the absence of alterations in DNA sequences) may in part mediate the complex gene-by-environment interactions that can lead to asthma. The variable natural history of asthma (i.e., incidence and remission of symptoms) may be a result of epigenetic changes, such as DNA methylation, covalent histone modifications, microRNA changes, and chromatin alterations, after early or later environmental exposures. Findings from multiple epidemiologic and experimental studies indicate that asthma risk may be modified by epigenetic regulation. One study suggested that the transmission of asthma risk may occur across multiple generations. Experimental studies provide substantial in vitro data indicating that DNA methylation of genes critical to T-helper cell differentiation may induce polarization toward or away from an allergic phenotype. Despite this initial progress, fundamental questions remain that need to be addressed by well-designed research studies. Data generated from controlled experiments using in vivo models and/or clinical specimens collected after environmental exposure monitoring are limited. Importantly, cohort-driven epigenetic research has the potential to address key questions, such as those concerning the influence of timing of exposure, dose of exposure, diet, and ethnicity on susceptibility to asthma development. There is immense promise that the study of environmental epigenetics will help us understand a theoretically preventable environmental disease.
epigenetics; asthma; DNA methylation; gene–environment interactions
Recently, epigenetic-mediated mechanisms — which involve heritable changes in gene expression in the absence of alterations in DNA sequences — have been proposed as contributing to asthma. In this issue of the JCI, Hollingsworth and colleagues report on the effect of prenatal maternal dietary intake of methyl donors on the risk of allergic airway disease in offspring in mice and show that these effects involve epigenetic regulation (see the related article beginning on page 3462). Supplementation of the maternal diet with methyl donors was associated with greater airway allergic inflammation and IgE production in F1 and, to some extent, F2 progeny. Site-specific differences in DNA methylation and reduced transcriptional activity were detected. If these findings are confirmed, a new paradigm for asthma pathogenesis may be emerging.
Exposure of black carbon (BC) is associated with a variety of adverse health outcomes. A number of optical methods for estimating BC on Teflon filters have been adopted but most assume all light absorption is due to BC while other sources of colored particulate matter exist. Recently, a four-wavelength-optical reflectance measurement for distinguishing second hand cigarette smoke (SHS) from soot-BC was developed (Brook et al., 2010; Lawless et al., 2004). However, the method has not been validated for soot-BC nor SHS and little work has been done to look at the methodological issues of the optical reflectance measurements for samples that could have SHS, BC, and other colored particles. We refined this method using a lab-modified integrating sphere with absorption measured continuously from 350 nm to 1000 nm. Furthermore, we characterized the absorption spectrum of additional components of particulate matter (PM) on PM2.5 filters including ammonium sulfate, hematite, goethite, and magnetite. Finally, we validate this method for BC by comparison to other standard methods. Use of synthesized data indicates that it is important to optimize the choice of wavelengths to minimize computational errors as additional components (more than 2) are added to the apportionment model of colored components. We found that substantial errors are introduced when using 4 wavelengths suggested by Lawless et al. to quantify four substances, while an optimized choice of wavelengths can reduce model-derived error from over 10% to less than 2%. For environmental samples, the method was sensitive for estimating airborne levels of BC and SHS, but not mass loadings of iron oxides and sulfate. Duplicate samples collected in NYC show high reproducibility (points consistent with a 1:1 line, R2 = 0.95). BC data measured by this method were consistent with those measured by other optical methods, including Aethalometer and Smoke-stain Reflectometer (SSR); although the SSR looses sensitivity at filter loadings above 90 ng/mm2. Furthermore, positive correlations (R2 = 0.7) were observed between EC measured by NIOSH Method 5040 on quartz filters and BC measured in co-located Teflon filter samples collected from both heating and non-heating seasons. Overall, the validation data demonstrates the usefulness of this method to evaluate BC from archived Teflon filters while potentially providing additional component information.
Prenatal Paracetamol (Acetaminophen) has been associated with increased risk of allergic disease in early childhood, an association that could be due to increased altered susceptibility induced by air pollutants. The main goal of the study was to test the hypothesis that prenatal Paracetamol exposure increases the risk of developing eczema in early childhood and that this association is stronger for children who are exposed prenatally to higher concentrations of fine particulate matter (PM2.5). The study sample consisted of 322 women recruited from January 2001 to February 2004 in the Krakow inner city area who gave birth to term babies and completed 5-year follow-up. Paracetamol use in pregnancy was collected by interviews and prenatal personal exposure to over 48 hours was measured in all recruited women in the second trimester of PM2.5 pregnancy. After delivery, every three months in the first 24 months of the newborn’s life and every 6 months later, a detailed standardized face-to-face interview on the infant’s health was administered to each mother by a trained interviewer. During the interviews at each of the study periods after birth, a history of eczema was recorded.
By Cox proportional hazard regression, prenatal exposure to Paracetamol increased the risk of eczema by 20% and PM2.5 by 6%, albeit non significantly. However, the the joint exposure to Paracetamol and higher prenatal PM2.5 was significant and doubled the risk of eczema symptoms (HR = 2.07, 95%CI: 1.01 – 4.34). The findings suggest that even very small doses of Paracetamol in pregnancy may affect the occurrence of allergy outcomes such as eczema in early childhood but only at the co-exposure to higher fine particulate matter.
birth cohort study; eczema; children; acetaminophen; pregnancy; prenatal fine particulate matter
Exposures to ambient air traffic-related pollutants and their sources have been associated with respiratory and asthma morbidity in children. However, longitudinal investigation of the effects of traffic-related exposures during early childhood is limited. We examined associations of residential proximity and density of traffic and stationary sources of air pollution with wheeze, asthma, and immunoglobulin (Ig) E among New York City children between birth and age 5 years.
Subjects included 593 Dominican and African American participants from the Columbia Center for Children’s Environmental Health cohort. Prenatally, through age 5 years, residential and respiratory health data were collected every 3-6 months. At ages 2, 3, and 5 years, serum IgE was measured. Spatial data on the proximity and density of roadways and built environment were collected for a 250 meter buffer around subjects’ homes. Associations of wheeze, asthma, total IgE, and allergen-specific IgE with prenatal, earlier childhood, and concurrent exposures to air pollution sources were analyzed using generalized estimating equations or logistic regression. In repeated measures analyses, concurrent residential density of four-way intersections was associated significantly with wheeze (odds ratio: 1.26; 95% confidence interval [CI]: 1.01, 1.57). Age 1 exposures also were associated with wheeze at subsequent ages. Concurrent proximity to highway was associated more strongly with total IgE (ratio of the geometric mean levels: 1.25; 95% CI: 1.09, 1.42) than were prenatal or earlier childhood exposures. Positive associations also were observed between percent commercial building area and asthma, wheeze, and IgE and between proximity to stationary sources of air pollution and asthma.
Longitudinal investigation suggests that among Dominican and African American children living in Northern Manhattan and South Bronx during ages 0 to 5 years, residence in neighborhoods with high density of traffic and industrial facilities may contribute to chronic respiratory morbidity, and concurrent, prenatal, and earlier childhood exposures may be important. These findings may have broad implications for other urban populations that commonly have high asthma prevalence and exposure to a high density of traffic and stationary air pollution sources.
Traffic; Asthma; IgE; Geographic information systems; Air pollution
Incomplete combustion produces a pollutant mixture that includes polycyclic aromatic hydrocarbons (PAHs). Previous work by the Columbia Center for Children's Environmental Health (CCCEH) and others linked exposure to PAH with symptoms of asthma and other adverse health effects in young children. Inhaled β2-adrenergic agonists are mainstays in the treatment of reactive airway diseases. These exogenous catecholamines engage membrane-bound β2-adrenergic receptors (β2AR) on airway epithelial and smooth muscle cells to cause airway dilation. We hypothesized that exposure to PAH might similarly interfere with the function of β2AR in airway epithelial or smooth muscle cells, reducing the efficacy of a medication important for the treatment of asthma symptoms. A PAH mixture was devised, based on ambient levels measured prenatally among a cohort of pregnant women participating at the CCCEH. Primary airway epithelial and smooth muscle cells were exposed to varying concentrations of the PAH mixture, and expression, function, and signaling of β2AR were assessed. Murine tracheal epithelial cells and human airway smooth muscle cells, after exposure to a PAH mixture, exhibited reduced expression and function of β2AR. These findings support our hypothesis that environmentally relevant PAHs can impede β2AR-mediated airway relaxation, and suggest a new paradigm where air pollutants not only contribute to the pathogenesis of childhood asthma, but also diminish responsiveness to standard therapy.
polycyclic aromatic hydrocarbons; β2-adrenergic receptors
Background: Recent cross-sectional studies suggest a link between butylbenzyl phthalate (BBzP) in house dust and childhood eczema.
Objectives: We aimed to evaluate whether concentrations of monobenzyl phthalate (MBzP), the main BBzP metabolite in urine, during pregnancy are associated prospectively with eczema in young children, and whether this association varies by the child’s sensitization to indoor allergens or serological evidence of any allergies.
Methods: MBzP was measured in spot urine samples during the third trimester of pregnancy from 407 African-American and Dominican women residing in New York City in 1999–2006. Repeated questionnaires asked mothers whether their doctor ever said their child had eczema. Child blood samples at 24, 36, and 60 months of age were analyzed for total, anti-cockroach, dust mite, and mouse IgE. Relative risks (RR) were estimated with multivariable modified Poisson regression. Analyses included a multinomial logistic regression model for early- and late-onset eczema versus no eczema through 60 months of age.
Results: MBzP was detected in > 99% of samples (geometric mean = 13.6; interquartile range: 5.7–31.1 ng/mL). By 24 months, 30% of children developed eczema, with the proportion higher among African Americans (48%) than among Dominicans (21%) (p < 0.001). An interquartile range increase in log MBzP concentration was associated positively with early-onset eczema (RR = 1.52 for eczema by 24 months; 95% confidence interval: 1.21, 1.91, p = 0.0003, n = 113 reporting eczema/376 total sample), adjusting for urine specific gravity, sex, and race/ethnicity. MBzP was not associated with allergic sensitization, nor did seroatopy modify consistently the MBzP and eczema association.
Conclusions: Prenatal exposure to BBzP may influence the risk of developing eczema in early childhood.
butylbenzyl phthalate; eczema; plasticizers
Secondhand smoke (SHS) and ambient air pollution (AAP) exposures have been associated with increased prevalence and severity of asthma and DNA modifications of immune cells. In the current study, we examined the association between SHS and AAP with DNA methylation and expression of interferon-gamma (IFN-γ) and forkhead box protein 3 (Foxp3) in T cell populations.
Subjects 7–18 years old were recruited from Fresno (high AAP; n = 62) and Stanford, CA (low AAP; n = 40) and divided into SHS-exposed (Fresno: n = 31, Stanford: n = 6) and non-SHS-exposed (nSHS; Fresno: n = 31, Stanford: n = 34) groups. T cells purified from peripheral blood were assessed for levels of DNA methylation and expression of IFN-γ (in effector T cells) or Foxp3 (in regulatory T cells).
Analysis showed a significant increase in mean % CpG methylation of IFN-γ and Foxp3 associated with SHS exposure (IFN-γ: FSHS 62.10%, FnSHS 41.29%, p < 0.05; SSHS 46.67%, SnSHS 24.85%, p < 0.05; Foxp3: FSHS 74.60%, FnSHS 54.44%, p < 0.05; SSHS 62.40%, SnSHS 18.41%, p < 0.05) and a significant decrease in mean transcription levels of both genes (IFN-γ: FSHS 0.75, FnSHS 1.52, p < 0.05; SHS 2.25, nSHS 3.53, p < 0.05; Foxp3: FSHS 0.75, FnSHS 3.29, p < 0.05; SSHS 4.8, SnSHS 7.2, p < 0.05). AAP was also associated with hypermethylation (IFN-γ: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05; Foxp3: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05) and decreased transcription of both genes (IFN-γ: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05; Foxp3: FSHS vs. SSHS, p < 0.05; FnSHS vs. SnSHS, p < 0.05). Average methylation between AAP- and SHS-only exposures was not significantly different (IFN-γ: p = 0.15; Foxp3: p = 0.27), nor was Foxp3 expression (p = 0.08); IFN-γ expression was significantly decreased in AAP-only subjects (p < 0.05).
Exposures to SHS and AAP are associated with significant hypermethylation and decreased expression of IFN-γ in Teffs and Foxp3 in Tregs. Relative contributions of each exposure to DNA modification and asthma pathogenesis warrant further investigation.
Secondhand smoke; Ambient air pollution; IFN-γ; Foxp3; Methylation; Epigenetic regulation; Pediatrics; T effectors; T regulatory cells
Background: Maternal factors are implicated in the onset of childhood asthma. Differentiation of naïve CD4+ T lymphocytes into pro-allergic T-helper 2 cells induces interleukin (IL)4 expression and inhibits interferon (IFN)γ expression accompanied by concordant methylation changes in the promoters of these genes. However, it has yet to be established whether maternal exposure to polycyclic aromatic hydrocarbons (PAHs) can alter these gene promoters epigenetically during fetal development.
Objectives: In this study we sought to elucidate the relationship between maternal PAH exposure and promoter methylation status of IFNγ and IL4.
Methods: We assessed the effects of benzo[a]pyrene (BaP), a representative airborne PAH, on the methylation status of the IFNγ and IL4 promoters in Jurkat cells and two lung adenocarcinoma cell lines, and on gene expression. In addition, we evaluated methylation status of the IFNγ promoter in cord white blood cells from 53 participants in the Columbia Center for Children’s Environmental Health cohort. Maternal PAH exposure was estimated by personal air monitoring during pregnancy.
Results: In vitro exposure of the cell models to low, noncytotoxic doses (0.1 and 1 nM) of BaP elicited increased promoter hypermethylation and reduced expression of IFNγ, but not IL4. IFNγ promoter methylation in cord white blood cells was associated with maternal PAH exposure in the cohort study subsample.
Conclusion: Consistent with the results for the cell lines, maternal exposure to PAHs was associated with hypermethylation of IFNγ in cord blood DNA from cohort children. These findings support a potential role of epigenetics in fetal reprogramming by PAH-induced environmental diseases.
cord white blood cell; cytokines; DNA methylation; epigenetic epidemiology; epigenetics; fetal origins of disease; interferon-γ; interleukin 4
Genomic imprinting is a form of epigenetic regulation in mammals in which the same allele of a gene is expressed differently depending on the parental origin of the allele. Traditionally, the detection of imprinted genes that affect complex diseases has been focused on linkage designs with pedigrees or case-parent designs with case-parent trios. In the past two decades, the birth cohort design with mother-offspring pairs has been applied to understand better the effect of environmental influences during pregnancy and beginning of life on the growth and development of children. No work has been done on the detection of imprinted genes using birth cohort designs. Moreover, although the importance of imprinting has been well recognized, no study has looked at how environmental exposures modify the effects of imprinted genes. In this study, we show that the proposed imprinting test using the birth cohort design with mother-offspring pairs is an efficient test for testing the interactions between imprinted genes and environmental exposures. Through extensive simulation studies and a real data application, the proposed imprinting test has demonstrated much improved power in detecting gene-environment in teractions than that of a test assuming the Mendelian dominant model when the true underlying genetic model is imprinting.
Mother-offspring pairs; Genetic imprinting; igene-environment interaction
To advance asthma cohort research, we need a method that can use longitudinal data, including when collected at irregular intervals, to model multiple phenotypes of wheeze and identify both time-invariant (eg, sex) and time-varying (eg, environmental exposure) risk factors.
To demonstrate the use of latent class growth analysis (LCGA) in defining phenotypes of wheeze and examining the effects of causative factors, using repeated questionnaires in an urban birth cohort study.
We gathered repeat questionnaire data on wheeze from 689 children ages 3 through 108 months (n = 7,048 questionnaires) and used LCGA to identify wheeze phenotypes and model the effects of time-invariant (maternal asthma, ethnicity, prenatal environmental tobacco smoke, and child sex) and time-varying (cold/influenza [flu] season) risk factors on prevalence of wheeze in each phenotype.
LCGA identified four wheezing phenotypes: never/infrequent (47.1%), early-transient (37.5%), early-persistent (7.6%), and late-onset (7.8%). Compared with children in the never/infrequent phenotype, maternal asthma was a risk factor for the other 3 phenotypes; Dominican versus African American ethnicity was a risk factor for the early-transient phenotype; and male sex was a risk factor for the early-persistent phenotype. The prevalence of wheeze was higher during the cold/flu season than otherwise among children in the early-persistent phenotype (P = .08).
This is the first application of LCGA to identify wheeze phenotypes in asthma research. Unlike other methods, this modeling technique can accommodate questionnaire data collected at irregularly spaced age intervals and can simultaneously identify multiple trajectories of health outcomes and associations with time-invariant and time-varying causative factors.
As there is a scarcity of evidence on potential hazards and preventive factors for infantile eczema operating in the prenatal period, the main goal of this study was to assess the role of prenatal exposure to fine particulate matter and environmental tobacco smoke (ETS) in the occurrence of infant eczema jointly with the possible modulating effect of maternal fish consumption.
The study sample consisted of 469 women enrolled during pregnancy, who gave birth to term babies (>36 weeks of gestation). Among all pregnant women recruited, personal measurements of fine particulate matter (PM2.5) were performed over 48 h in the second trimester of pregnancy. After delivery, every 3 months in the first year of the newborn's life, a detailed, standardized, face-to-face interview was administered to each mother, in the process of which a trained interviewer recorded any history of infantile eczema and data on potential environmental hazards. The estimated risk of eczema related to higher prenatal exposure to fine particulate matter (PM2.5 >53.0 μg/m3) and postnatal ETS as well as the protective effect of maternal fish intake were adjusted for potential confounders in a multivariable logistic regression model.
While the separate effects of higher prenatal PM2.5 and postnatal ETS exposure were not statistically significant, their joint effect appeared to have a significant influence on the occurrence of infantile eczema [odds ratio 2.39, 95% confidence interval (CI) 1.10–5.18]. With maternal fish intake of more than 205 g/week, the risk of eczema decreased by 43% (odds ratio 0.57, 95% CI 0.35–0.93). The incidence rate ratio (IRR) for eczema symptoms, estimated from the Poisson regression model, was increased with both higher exposure to prenatal PM2.5 and postnatal ETS (IRR 1.55, 95% CI 0.99–2.44) and in children of atopic mothers (IRR 1.35, 95% CI 1.04–1.75) but was lower in girls (IRR 0.78, 95% CI 0.61–1.00). The observed preventive effect of fish consumption on the frequency of eczema symptoms was consistent with the results of the logistic analysis (IRR 0.72, 95% CI 0.52–0.99).
The findings indicate that higher prenatal exposure to fine particulate matter combined with postnatal exposure to ETS may increase the risk of infant eczema, while maternal fish intake during pregnancy may reduce the risk of infantile eczema.
Fish consumption; Prenatal exposure to fine particles; Cow's milk allergy; Passive tobacco smoke; Cohort study
Previously, we reported that prenatal exposures to polycyclic aromatic hydrocarbons (PAH) and postnatal environmental tobacco smoke (ETS) in combination were associated with respiratory symptoms at ages 1 and 2 years. Here, we hypothesized that children exposed to both prenatal PAH and ETS may be at greater risk of asthma and seroatopy at ages 5 to 6 years, after controlling for current pollution exposure.
Prenatal PAH exposure was measured by personal air monitoring over 48 hrs. ETS exposure, respiratory symptoms and asthma at ages 5–6 years were assessed through questionnaire. Immunoglobulin (Ig) E was measured by Immunocap.
A significant interaction between prenatal PAH and prenatal (but not postnatal) ETS exposure on asthma (p<0.05), but not IgE, was detected. Among children exposed to prenatal ETS, a positive nonsignificant association was found between prenatal PAH exposure and asthma (OR 1.96, 95% CI [0.95–4.05]). Among children without exposure to prenatal ETS, a negative nonsignificant association was found between prenatal PAH exposure and asthma (OR 0.65, 95% CI [0.41–1.01]). Prenatal PAH exposure was not associated with asthma or IgE at age 5 to 6 years.
Combined prenatal exposure to PAH and ETS appears to be associated with asthma but not seroatopy at age 5–6. Exposure to PAH alone does not appear associated with either asthma or seroatopy at age 5 to 6 years. Discerning the differential effects between ETS exposed and ETS nonexposed children requires further study.
Premature delivery is often complicated by neonatal growth restriction and neurodevelopmental impairment. Because global over-nutrition increases the risk of adult metabolic syndrome, we sought a targeted intervention. Premature delivery and perinatal growth restriction decrease circulating levels of the neurotrophic hormone leptin. We hypothesized leptin supplementation would normalize the outcomes of mice with incipient neonatal growth restriction. Pups were fostered into litters of 6 or 12 to elicit divergent growth patterns. Pups in each litter received injections of saline or leptin from day 4–14. At 4 months, mice underwent tail cuff blood pressure measurement, behavioral testing and MRI. Mice fostered in litters of 12 had decreased weanling weights and leptin levels. Neonatal leptin administration normalized plasma leptin levels without influencing neonatal growth. Leptin replacement also normalized the hypertension, stress-linked immobility, conditioned fear, and amygdala enlargement seen in neonatal growth restricted male mice. In control males, neonatal leptin administration led to hypothalamic enlargement, without overt neurocardiovascular alterations. Female mice were less susceptible to the effects of neonatal growth restriction or leptin supplementation. In conclusion, the effects of neonatal leptin administration are modulated by concurrent growth and gender. In growth restricted male mice, physiologic leptin replacement improves adult neurocardiovascular outcomes.
SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate immunoglobulin heavy chain class switching to IgE. Analysis of mice with mutations in the SOCS-1 gene demonstrated that IgE levels increase with loss of SOCS-1 alleles. This suggested that overall SOCS-1 acts as an inhibitor of IgE expression in vivo. A genetic association study was performed in 474 children enrolled in the Tucson Children’s Respiratory Study to determine if genetic variation in the SOCS-1 locus correlates with altered levels of IgE. Carriers of the C-allele for a novel, 3′ genomic single nucleotide polymorphism (SNP) in the SOCS-1 gene (SOCS1+1125G>C; rs33932899) were found to have significantly lower levels of serum IgE as compared with homozygotes for the G-allele. Analysis demonstrated that the SOCS1+1125G>C SNP was in complete linkage disequilibrium with a SNP at position SOCS1−820G>T (rs33977706) of the SOCS-1 promoter. Carriers of the T-allele at the SOCS1−820G>T were also found to be associated with. The promoter SNP increased transcriptional activity of the SOCS-1 promoter in reporter assays and human B cells. Consistent with this observation, the presence of this polymorphism within the promoter abolished binding of Yin-Yang-1, which is identified as a negative regulator of SOCS-1 transcriptional activity. These data suggest that genetic variation in the SOCS-1 promoter may affect IgE production.
Several in vivo and in vitro studies have shown that metal-rich particles may enhance allergic responses to house dust mites and induce an increased release of allergy-related cytokines.
The main goal of this analysis is to define the possible association of intrauterine exposure to lead and mercury with the occurrence of skin sensitization to common aeroallergens in early childhood.
Material and Methods
The present study refers to a sample of 224 women in the second trimester of pregnancy recruited from Krakow inner city area who had full term pregnancies and whose children underwent skin prick testing (SPT) at the age of 5. Lead and mercury levels were assessed in cord blood and retested in children at age of 5 years. Aeroallergen concentrations in house dust were measured at the age of 3 years. The main health outcome (atopic status) was defined as the positive SPT to at least one common aeroallergen (Der f1, Der p1, Can f1 and Fel d1) at the age of 5 years. In the statistical analysis of the association between atopic status of children and exposure to metals, the study considered a set of covariates such as maternal characteristics (age, education, atopy), child’s gender, number of older siblings, prenatal (measured via cord blood cotinine) and postnatal environmental tobacco smoke together with exposure to polycyclic aromatic hydrocarbons (PAH) as measured by PAH-DNA adducts.
Results and conclusion
In the binary regression analysis, which controlled for the confounders, the risk ratio (RR) estimate for atopic sensitization was significantly associated with the lead exposure (RR =2.25, 95%CI: 1.21–4.19). In conclusion, the data suggest that even very low-level of prenatal lead exposure may be implicated in enhancing sensitization to common aeroallergens in early childhood.
birth cohort study; lead; intrauterine exposure; atopy; children
Objectives and Hypothesis
To determine the feasibility of using a multiple flow offline fractional exhaled nitric oxide (FeNO) collection method in an inner-city cohort and determine this population’s alveolar and conducting airway contributions of NO. We hypothesized that the flow independent NO parameters would be associated differentially with wheeze and seroatopy.
As part of a birth cohort study, 9-year-old children (n = 102) of African-American and Dominican mothers living in low-income NYC neighborhoods had FeNO samples collected offline at constant flow rates of 50, 83, and 100 ml/sec. Seroatopy was defined as having measurable (≥0.35 IU/ml) specific IgE to any of the five inhalant indoor allergens tested. Current wheeze (last 12 months) was assessed by ISAAC questionnaire. Bronchial NO flux (JNO) and alveolar NO concentration (Calv) were estimated by the Pietropaoli and Hogman methods.
Valid exhalation flow rates were achieved in 96% of the children. Children with seroatopy (53%) had significantly higher median JNO (522 pl/sec vs. 161 pl/sec, P < 0.001) when compared to non-seroatopic children; however, median Calv was not significantly different between these two groups (5.5 vs. 5.8, P= 0.644). Children with wheeze in the past year (21.6%) had significantly higher median Calv (8.4 ppb vs. 4.9 ppb, P < 0.001), but not JNO (295 pl/sec vs. 165 pl/sec, P = 0.241) when compared with children without wheeze. These associations remained stable after adjustment for known confounders/covariates.
The multiple flow method was easily implemented in this pediatric inner-city cohort. In this study population, alveolar concentration of NO may be a better indicator of current wheeze than single flow FeNO.
asthma; atopy; offline FeNO method; alveolar NO; bronchial flux
Exposure to air pollutants has been associated with adverse health effects. However, analyses of the effects of season and ambient parameters such as ozone have not been fully conducted. Residential indoor and outdoor air levels of polycyclic aromatic hydrocarbons (PAH), black carbon (measured as absorption coefficient [Abs]), and fine particulate matter <2.5 μm (PM)2.5 were measured over two-weeks in a cohort of 5–6 year old children (n=334) living in New York City’s Northern Manhattan and the Bronx between October 2005 and April 2010. The objectives were to: 1) characterize seasonal changes in indoor and outdoor levels and indoor/outdoor (I/O) ratios of PAH (gas + particulate phase; dichotomized into Σ8PAHsemivolatile (MW 178–206), and Σ8PAHnonvolatile (MW 228–278)), Abs, and PM2.5; and 2) assess the relationship between PAH and ozone. Results showed that heating compared to nonheating season was associated with greater Σ8PAHnonvolatile (p<0.001) and Abs (p<0.05), and lower levels of Σ8PAHsemivolatile (p<0.001). In addition, the heating season was associated with lower I/O ratios of Σ8PAHnonvolatile and higher I/O ratios of Σ8PAHsemivolatile (p<0.001) compared to the nonheating season. In outdoor air, Σ8PAHnonvolatile was correlated negatively with community-wide ozone concentration (p<0.001). Seasonal changes in emission sources, air exchanges, meteorological conditions and photochemical/chemical degradation reactions are discussed in relationship to the observed seasonal trends.
Nonvolatile PAH; I/O ratio; Heating season; Degradation; Inner-city children