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Study objective: Inner-city asthma is a growing problem, and concerns remain about the role of exposure to multiple indoor allergens. Because of the increasing problems of rat infestation in New York and other cities, we sought to determine the frequency of sensitization to rat among inner-city children with asthma living in homes infested with cockroaches, and whether rat sensitization is associated with increased symptoms. Design/Setting/Participants: As part of the Columbia Intervention to Reduce Indoor Allergens Study, 37 Latino and African-American children age 5–18 years with asthma and determined to have positive skin tests to cockroach were evaluated for the presence of sensitization to rat by skin test and anti-rat-IgE levels. Clinical course was assessed by questionnaire. Results: We found that 43% had positive skin tests to rat, and 43% had an elevated anti-rat-IgE level. Anti-rat-IgE levels correlated with anti-cockroach-IgE levels (r =. 37, p =. 02) and mouse-IgE levels (r =. 72, p =. 001). O...

Rates of developmental and respiratory diseases are disproportionately high in underserved, minority populations such as those in New York City's Washington Heights, Harlem, and the South Bronx. Blacks and Latinos in these neighborhoods represent high risk groups for asthma, adverse birth outcomes, impaired development, and some types of cancer. The Columbia Center for Children's Environmental Health in Washington Heights uses molecular epidemiologic methods to study the health effects of urban indoor and outdoor air pollutants on children, prenatally and postnatally, in a cohort of over 500 African-American and Dominican (originally from the Dominican Republic) mothers and newborns. Extensive data are collected to determine exposures to particulate matter < 2.5 microm in aerodynamic diameter (PM(2.5)), polycyclic aromatic hydrocarbons (PAHs), diesel exhaust particulate (DEP), nitrogen oxide, nonpersistent pesticides, home allergens (dust mite, mouse, cockroach), environmental tobacco smoke (ETS), and lead and other metals. Biomarkers, air sampling, and clinical assessments are used to study the effects of these exposures on children's increased risk for allergic sensitization, asthma and other respiratory disorders, impairment of neurocognitive and behavioral development, and potential cancer risk. The center conducts its research and community education in collaboration with 10 community-based health and environmental advocacy organizations. This unique academic-community partnership helps to guide the center's research so that it is most relevant to the context of the low-income, minority neighborhoods in which the cohort resides, and information is delivered back to these communities in meaningful ways. In turn, communities become better equipped to relay environmental health concerns to policy makers. In this paper we describe the center's research and its academic-community partnership and present some preliminary findings.

Importance Polycyclic aromatic hydrocarbons are widespread urban air pollutants from combustion of fossil fuel and other organic material shown previously to be neurotoxic. Objective In a prospective cohort study, we evaluated the relationship between Attention Deficit Hyperactivity Disorder behavior problems and prenatal polycyclic aromatic hydrocarbon exposure, adjusting for postnatal exposure. Materials and Methods Children of nonsmoking African-American and Dominican women in New York City were followed from in utero to 9 years. Prenatal polycyclic aromatic hydrocarbon exposure was estimated by levels of polycyclic aromatic hydrocarbon- DNA adducts in maternal and cord blood collected at delivery. Postnatal exposure was estimated by the concentration of urinary polycyclic aromatic hydrocarbon metabolites at ages 3 or 5. Attention Deficit Hyperactivity Disorder behavior problems were assessed using the Child Behavior Checklist and the Conners Parent Rating Scale- Revised. Results High prenatal adduct exposure, measured by elevated maternal adducts was significantly associated with all Conners Parent Rating Scale-Revised subscales when the raw scores were analyzed continuously (N = 233). After dichotomizing at the threshold for moderately to markedly atypical symptoms, high maternal adducts were significantly associated with the Conners Parent Rating Scale-Revised DSM-IV Inattentive (OR = 5.06, 95% CI [1.43, 17.93]) and DSM-IV Total (OR = 3.37, 95% CI [1.10, 10.34]) subscales. High maternal adducts were positivity associated with the DSM-oriented Attention Deficit/Hyperactivity Problems scale on the Child Behavior Checklist, albeit not significant. In the smaller sample with cord adducts, the associations between outcomes and high cord adduct exposure were not statistically significant (N = 162). Conclusion The results suggest that exposure to polycyclic aromatic hydrocarbons encountered in New York City air may play a role in childhood Attention Deficit Hyperactivity Disorder behavior problems.

Exposure to airborne black carbon (BC) has been associated with asthma development, respiratory symptoms and decrements in lung function. However, the mechanism through which BC may lead to respiratory symptoms has not been completely elucidated. Oxidative stress has been suggested as a potential mechanism through which BC might lead to adverse health outcomes. Exhaled breath condensate (EBC) allows for the non-invasive collection of airway lining fluid containing biomarkers of oxidative stress like 8-isoprostane, a stable by-product of lipid peroxidation. Therefore, we sought to characterize the association between domestic airborne BC concentrations and 8-isoprostane in EBC.Seven- and eight-year-old children participated in an asthma case-control study in New York City. During home visits, air samples and EBC were collected. Seven day averages of domestic levels of particulate matter2.5μm (PM2.5), BC and environmental tobacco smoke (ETS) were measured. Urea and 8-isoprostane were measured by liquid chromatography tandem mass spectrometry (LC/MS/MS) in EBC.In univariate models, PM2.5 and BC, but not ETS, were significantly associated with increases in 8-isoprostane in the EBC (β=0.006 and β=0.106 respectively, p0.05 for both). These associations remained statistically significant for both PM2.5 and BC after adjustment for covariates. In a co-pollutant model including PM2.5, BC and ETS, only BC remained a statistically significant predictor of 8-isoprostane (p0.05).Our findings suggest the BC fraction of PM might contain exposure relevant to increased oxidative stress in the airways.

Background Asthma is associated with allergic sensitization in about half of all cases, and asthma phenotypes can vary by age and sex. DNA methylation in the promoter of the allergy regulatory gene interferon gamma (IFNγ) has been linked to the maintenance of allergic immune function in human cell and mouse models. We hypothesized that IFNγ promoter methylation at two well-studied, key cytosine phosphate guanine (CpG) sites (-186 and -54), may differ by age, sex, and airway versus systemic tissue in a cohort of 74 allergic asthmatics. Results After sampling buccal cells, a surrogate for airway epithelial cells, and CD4+ lymphocytes, we found that CD4+ lymphocyte methylation was significantly higher in children compared to adults at both CpG sites (P

This paper reports on validation experiments with the recently developed microAeth®, a pocket-sized device which is able to obtain real-time and personal measurements of black carbon (BC) aerosol. High reproducibility was observed when comparing the results from six new individual units during fixed-site monitoring out of a window (relative standard deviation [RSD] = 8% ± 5%, N = 1442). The results obtained from the microAeth devices agreed with those obtained from a full size rack mounted Aethalometer, based on both the 1-minute data (R = 0.92, slope = 1.01 ± 0.01, N = 1380) and 24-h average data. The 24-h average of real time data obtained from the microAeths was comparable to the BC concentration obtained from 24-h integrated PM2.5 filter deposits, as determined by multi-wavelength optical absorption (R = 0.98, slope = 0.92 ± 0.07, N = 12). Rapid environmental changes in relative humidity (RH) and temperature (T) can result in false positive and negative peaks in the real time BC concentrations, though averages > 1–2-hour are only minimally affected. An inlet with a diffusion drier based on Nafion® tubing was developed in order to use BC data with a high time resolution. The data shows that the diffusion drier greatly reduce the impacts from rapid changes in RH and T when the monitoring system is worn in close proximity to the body (e.g., in the vest pocket).

Background: Exposure to air pollutants including polycyclic aromatic hydrocarbons (PAH), and specifically pyrene from combustion of fuel oil, coal, traffic and indoor sources, has been associated with adverse respiratory health outcomes. However, time trends of airborne PAH and metabolite levels detected via repeat measures over time have not yet been characterized. We hypothesized that PAH levels, measured repeatedly from residential indoor and outdoor monitors, and children׳s urinary concentrations of PAH metabolites, would decrease following policy interventions to reduce traffic-related air pollution. Methods: Indoor PAH (particle- and gas-phase) were collected for two weeks prenatally (n=98), at age 5/6 years (n=397) and age 9/10 years (n=198) since 2001 and at all three age-points (n=27). Other traffic-related air pollutants (black carbon and PM2.5) were monitored indoors simultaneous with PAH monitoring at ages 5/6 (n=403) and 9/10 (n=257) between 2005 and 2012. One third of the homes were selected across seasons for outdoor PAH, BC and PM2.5 sampling. Using the same sampling method, ambient PAH, BC and PM2.5 also were monitored every two weeks at a central site between 2007 and 2012. PAH were analyzed as semivolatile PAH (e.g., pyrene; MW 178–206) (∑8PAHsemivolatile: Including pyrene (PYR), phenanthrene (PHEN), 1-methylphenanthrene (1-MEPH), 2-methylphenanthrene (2-MEPH), 3-methylphenanthrene (3-MEPH), 9-methylphenanthrene (9-MEPH), 1,7-dimethylphenanthrene (1,7-DMEPH), and 3,6-dimethylphenanthrene (3,6-DMEPH)) and the sum of eight nonvolatile PAH (∑8PAHnonvolatile: Including benzo[a]anthracene (BaA), chrysene/iso-chrysene (Chry), benzo[b]fluoranthene (BbFA), benzo[k]fluoranthene (BkFA), benzo[a]pyrene (BaP), indeno[1,2,3-c,d]pyrene (IP), dibenzo[a,h]anthracene (DahA), and benzo[g,h,i]perylene (BghiP); MW 228–278). A spot urine sample was collected from children at child ages 3, 5, 7 and 9 between 2001 and 2012 and analyzed for 10 PAH metabolites. Results: Modest declines were detected in indoor BC and PM2.5 levels between 2005 and 2012 (Annual percent change [APC]=−2.08% [p=0.010] and −2.18% [p=0.059] for BC and PM2.5, respectively), while a trend of increasing pyrene levels was observed in indoor and outdoor samples, and at the central site during the comparable time periods (APC=4.81%, 3.77% and 7.90%, respectively; p

RationaleGreater levels of prenatal exposure to polycyclic aromatic hydrocarbon (PAH) have been associated with childhood obesity in epidemiological studies. However, the underlying mechanisms are unclear.ObjectivesWe hypothesized that prenatal PAH over-exposure during gestation would lead to weight gain and increased fat mass in offspring and grand-offspring mice. Further, we hypothesized that altered adipose gene expression and DNA methylation in genes important to adipocyte differentiation would be affected.Materials and methodsPregnant dams were exposed to a nebulized PAH mixture versus negative control aerosol 5 days a week, for 3 weeks. Body weight was recorded from postnatal day (PND) 21 through PND60. Body composition, adipose cell size, gene expression of peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer-binding proteins (C/EBP) α, cyclooxygenase (Cox)-2, fatty acid synthase (FAS) and adiponectin, and DNA methylation of PPAR γ, were assayed in both the offspring and grand-offspring adipose tissue.FindingsOffspring of dams exposed to greater PAH during gestation had increased weight, fat mass, as well as higher gene expression of PPAR γ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ. Similar differences in phenotype and DNA methylation extended through the grand-offspring mice.ConclusionsGreater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.

Primary sensitization to antigens may occur prenatally. We hypothesized that high prenatal exposure to indoor antigens increases the risk for sensitization in newborns in New York City populations with increased risk for asthma. We also investigated whether maternal sensitization is required for in utero sensitization to occur. One hundred sixty-seven pregnant African American or Dominican women residing in northern Manhattan were recruited and antigen was measured from home dust. After delivery, newborn cord and maternal blood were assayed for IgE and mononuclear cell proliferation and cytokine production in response to antigen. Cockroach, mouse, but not dust mite antigens, were commonly elevated in the kitchens and pregnant mothers’ beds. Increased mononuclear cell proliferation occurred in 54% of newborns in response to cockroach, 25% in response to dust mite Dermatophagoides pteronyssinus , 40% in response to dust mite D. farinae , and 34% in response to mouse protein extracts. Antigeninduced mononuclear cell proliferation occurred in cord blood even in the absence of antigen-induced mononuclear cell proliferation in the mother. Proliferation in response to antigens did not correlate with IgE levels, but proliferation in response to dust mite extracts correlated with interluekin-5 (IL-5) production in cord blood. These results suggest that ( 1 ) high prenatal exposures to cockroach and mouse antigens are prevalent; ( 2 ) in utero sensitization to multiple indoor antigens is common, occurs to a different degree than maternal sensitization, and may involve IL-5 upregulation.

Background: Exposure to traffic-related air pollutants, including polycyclic aromatic hydrocarbons (PAHs) from traffic emissions and other combustion sources, and childhood obesity, have been implicated as risk factors for developing asthma. However, the interaction between these two on asthma among young urban children has not been studied previously. Methods: Exposure to early childhood PAHs was measured by two week residential indoor monitoring at age 5–6 years in the Columbia Center for Children's Environmental Health birth cohort (n=311). Semivolatile [e.g., methylphenanthrenes] and nonvolatile [e.g., benzo(a)pyrene] PAHs were monitored. Obesity at age 5 was defined as a body mass index (BMI) greater than or equal to the 95th percentile of the year 2000 age- and sex-specific growth charts (Center for Disease Control). Current asthma and recent wheeze at ages 5 and 7 were determined by validated questionnaires. Data were analyzed using a modified Poisson regression in generalized estimating equations (GEE) to estimate relative risks (RR), after adjusting for potential covariates. Results: Neither PAH concentrations or obesity had a main effect on asthma or recent wheeze. In models stratified by presence/absence of obesity, a significant positive association was observed between an interquartile range (IQR) increase in natural log-transformed 1-methylphenanthrene (RR [95% CI]: 2.62 [1.17–5.88] with IQRln=0.76), and 9-methylphenanthrene (2.92 [1.09–7.82] with IQRln=0.73) concentrations and asthma in obese children (n=63). No association in non-obese (n=248) children was observed at age 5 (Pinteraction

Although maternal atopy is a risk factor for the development of peanut allergy, this phenomenon has not been well characterized experimentally, and the mechanisms underlying offspring risk are unclear.We sought to determine whether offspring of mothers with peanut allergy (O-PAM mice) are more susceptible to peanut allergy than offspring of naive mothers (O-NM mice) in a murine model and, if so, whether the susceptibility is linked to TH2-biased epigenetic alterations.Five-week-old O-PAM and O-NM mice were intragastrically sensitized to and challenged with peanut. Serum peanut-specific IgE levels, plasma histamine levels, anaphylactic reactions, and splenocyte and MLN cell cytokine production were measured. DNA methylation levels of the Il4 gene promoter from splenocytes and MLN cells from sensitized offspring and splenocytes from unsensitized neonatal offspring were determined by means of pyrosequencing.O-PAM mice exhibited 3-fold higher peanut-specific IgE levels after peanut sensitization, as well as 5-fold higher histamine levels and significantly higher anaphylactic symptom scores after challenge than O-NM mice (P .05-.01). Cultured splenocytes and MLNs from O-PAM mice produced significantly more TH2 cytokines than cells from O-NM mice (P .05-.01). Cells from O-PAM mice exhibited significantly reduced DNA methylation at CpG sites of the Il4 gene promoter than cells from O-NM mice. DNA methylation levels were inversely correlated with IL-4 and IgE production. O-PAM neonatal splenocyte hypomethylation of the Il4 gene promoter was also present.This study is the first to demonstrate that increased susceptibility to peanut allergy in O-PAM mice is associated with epigenetic alteration of the Il4 gene promoter. This finding might provide insight into preventing the development of early-life allergy.

Height, mass and skeletal maturity (Fels method) were assessed in 135 elite youth soccer players aged 10.7-16.5 years (only two boys were11.0 years). Sample sizes, years of training and current weekly training volume by two-year age groups were: 11-12 years (n = 63), 2.6 +/- 1.0 years and 4.1 +/- 1.7 h; 13-14 years (n = 29), 3.1 +/- 1.6 years and 4.5 +/- 1.7 h; 15-16 years (n = 43), 4.7 +/- 2.4 years and 6.1 +/- 2.0 h. The oldest age group included members of the national youth team. Heights and masses were compared to US reference values, and skeletal age and chronological age were contrasted. The players were also classified as late, average ('on time') and early maturers on the basis of differences between skeletal and chronological age, with the average category including boys with skeletal ages within +/- 1 year of chronological age. The mean heights and masses of 11- to 12-year-old soccer players equalled the US reference values, while those of players aged 13-14 and 15-16 years were slightly above the reference values. The mean skeletal age approximated mean chronological age in players aged 11-12 years (12.4 +/- 1.3 and 12.3 +/- 0.5 years, respectively), while mean skeletal age was in advance of mean chronological age in the two older groups (14.3 +/- 1.2 and 13.6 +/- 0.7 years, respectively, in 13- to 14-year-olds; 16.7 +/- 1.0 and 15.8 +/- 0.4 years, respectively, in 15- to 16-year-olds). Seven boys in the oldest age group were already skeletally mature and were not included when calculating differences between skeletal and chronological age. The proportion of late maturing boys in this sample of elite soccer players decreased with increasing chronological age. Among 11- to 12-year-old players, the percentages of late and early maturing boys were equal at 21% (n = 13). Among 13- to 14-year-old players, the percentages of late and early maturing boys were 7% (n = 2) and 38% (n = 11) respectively, while among players aged 15-16 years the percentages of late and early maturing boys were 2% (n = 1) and 65% (n = 28) respectively. The results of this comparative analysis suggest that the sport of soccer systematically excludes late maturing boys and favours average and early maturing boys as chronological age and sport specialization increase. It is also possible that late maturing boys selectively drop-out of soccer as age and sport specialization increase.

Ann Marie Reardon, MAa,b, Matthew S. Perzanowski, PhDa,b, Robin M. Whyatt, DrPHa,b, Ginger L. Chew, ScDa,b, Frederica P. Perera, DrPHa,b, and Rachel. L. Miller, MDa,b,c Ann Marie Reardon: ; Matthew S. Perzanowski: ; Robin M. Whyatt: ; Ginger L. Chew: ; Frederica P. Perera: ; Rachel. L. Miller: rlm14@columbia.edu a Mailman School of Public Health, Columbia University b Columbia Center for Children’s Environmental Health c Columbia University College of Physicians and Surgeons, Division of Pulmonary, Allergy and Critical Care Medicine, New York, NY

Background: Recent data suggest that the regulation of class switching to IgE by cytokines is mediated by STAT transcription factors. The induction of IgE by IL-4 and IL-13 occurs through the activation of the intracellular signal-transducing protein Stat6, whereas the inhibition of IgE class switching by interferon-γ (IFN-γ) occurs through the activation of Stat1. Objective: We hypothesized that in extrinsic asthma or in cases of markedly elevated IgE (ie, hyperimmunoglobulin E [HIE]) increased levels of IgE may be associated with alterations in the cytokine levels or the activation of Stat6. Methods: PBMCs and sera from 8 patients with extrinsic asthma (mean IgE, 285 ± 100 IU/mL), 3 patients with HIE (mean IgE, 7050 ± 1122 IU/mL), and 14 nonatopic control subjects (mean IgE, 112 ± 28 IU/mL) were analyzed. Results: The mean IL-4 level detected by ELISA was much greater in patients with HIE than control subjects (88.6 ± 11.5 pg/mL vs 11.5 ± 7.1 pg/mL, P = .005), and increased IL-4 levels among patients with both asthma and HIE correlated with the increased IgE levels. In contrast, IL-13 levels were not elevated. Levels of Stat6 protein present in PBMCs did not differ in the patients and control subjects. Examination of Stat6 DNA-binding activity demonstrated no activation of IL-4 signaling in patients with either HIE or acute asthma. Interestingly, evidence for the presence of B cells that have already switched to IgE was seen in PBMCs of several patients with asthma or HIE. Conclusion: These results indicate that (1) IgE production in asthma and HIE usually is associated with elevated levels of IL-4, but not IL-13, in the peripheral blood; (2) the increased sera IL-4 levels in asthma and HIE are not sufficient to induce Stat6 activation in PBMCs; and (3) evidence of switch recombination to ϵ may be detected in isolated cases of elevated IgE. This implies that high levels of IgE in these patients either results from B cells that have already undergone class switching, from Ig class switching that is localized to target tissues, or both. (J Allergy Clin Immunol 1998;102:503-11.)

Background/objectives Patients presenting with acute pulmonary embolism associated with hemodynamic compromise exhibit right ventricular enlargement and dysfunction on transthoracic echocardiogram. However, the degree of echocardiographic abnormalities among hemodynamically stable patients without preexisting cardiopulmonary disease during the acute stage of pulmonary embolism, and following treatment, is unknown. Therefore, this study was designed to assess the extent of right ventricular abnormalities detected on transthoracic echocardiogram in patients following acute pulmonary embolism and during treatment with anticoagulation or vena caval interruption. The extent of pulmonary vascular obstruction and complication rate on follow-up were also assessed. Design/interventions Sixty-four consecutive hemodynamically stable patients without preexisting known cardiopulmonary disorder presenting with acute pulmonary embolism and undergoing treatment with anticoagulation or inferior vena caval interruption were studied. All subjects underwent a two-dimensional transthoracic echocardiogram within 24 h of diagnosis. The degree of perfusion abnormality on lung scan was quantified. Twenty-six patients underwent follow-up echocardiogram and lung scan at 6 weeks. The echocardiographic findings were compared with those obtained from a group of normal control subjects matched for gender and age. Results Although the mean right ventricular end-diastolic areas did not differ (21.9±5.2 cm 2 vs 20.1±2.9 cm 2 for control subjects; p=not significant), the right ventricular end-systolic area was larger in comparison to our series of control subjects (14.6±5.1 cm 2 vs 11.7±2.0 cm 2 ; p=0.025). Fractional right ventricular area change was reduced in the patient group compared with the control subjects (34.3±9.0% vs 41.3±7.0%; p=0.003). The extent of right ventricular end-systolic area enlargement and decrease in fractional area change did not correlate with the degree of pulmonary vascular obstruction. Patients who were restudied at 6 weeks showed minimal improvement in echocardiographic findings, despite almost complete resolution of perfusion defects on lung scan. Conclusions The extent of right ventricular dysfunction in hemodynamically stable, previously normal patients with acute pulmonary embolism does not reflect the extent of the perfusion abnormalities. Further, right ventricular enlargement and systolic dysfunction are present and persistent despite treatment with heparin and warfarin therapy or vena caval interruption.

Background: Studies suggest that phthalate exposures may adversely affect child respiratory health. Objectives: We evaluated associations between asthma diagnosed in children between 5 and 11 years of age and prenatal exposures to butylbenzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), and diethyl phthalate (DEP). Methods: Phthalate metabolites were measured in spot urine collected from 300 pregnant inner-city women. Children were examined by an allergist or pulmonologist based on the first parental report of wheeze, other respiratory symptoms, and/or use of asthma rescue/controller medication in the preceding 12 months on repeat follow-up questionnaires. Standardized diagnostic criteria were used to classify these children as either having or not having current asthma at the time of the physician examination. Children without any report of wheeze or the other asthma-like symptoms were classified as nonasthmatics at the time of the last negative questionnaire. Modified Poisson regression analyses were used to estimate relative risks (RR) controlling for specific gravity and potential confounders. Results: Of 300 children, 154 (51%) were examined by a physician because of reports of wheeze, other asthma-like symptoms, and/or medication use; 94 were diagnosed with current asthma and 60 without current asthma. The remaining 146 children were classified as nonasthmatic. Compared with levels in nonasthmatics, prenatal metabolites of BBzP and DnBP were associated with a history of asthma-like symptoms (p < 0.05) and with the diagnosis of current asthma: RR = 1.17 (95% CI: 1.01, 1.35) and RR = 1.25 (95% CI: 1.04, 1.51) per natural log-unit increase, respectively. Risk of current asthma was > 70% higher among children with maternal prenatal BBzP and DnBP metabolite concentrations in the third versus the first tertile. Conclusion: Prenatal exposure to BBzP and DnBP may increase the risk of asthma among inner-city children. However, because this is the first such finding, results require replication. Citation: Whyatt RM, Perzanowski MS, Just AC, Rundle AG, Donohue KM, Calafat AM, Hoepner LA, Perera FP, Miller RL. 2014. Asthma in inner-city children at 5–11 years of age and prenatal exposure to phthalates: the Columbia Center for Children’s Environmental Health Cohort. Environ Health Perspect 122:1141–1146; http://dx.doi.org/10.1289/ehp.1307670

Asthma is a complex disease with genetic and environmental influences and emerging evidence suggests that epigenetic regulation is also a major contributor. Here, we focus on the developing paradigm that epigenetic dysregulation in asthma and allergy may start as early as in utero following several environmental exposures. We summarize the pathways important to the allergic immune response that are epigenetically regulated, the key environmental exposures associated with epigenetic changes in asthma genes, and newly identified epigenetic bio-markers that have been linked to clinical asthma. We conclude with a brief discussion about the potential to apply newly developing technologies in epigenetics to the diagnosis and treatment of asthma and allergy. The inherent plasticity of epigenetic regulation following environmental exposures offers opportunities for prevention using environmental remediation, measuring novel biomarkers for early identification of those at risk, and applying advances in pharmaco-epigenetics to tailor medical therapies that maximize efficacy of treatment. ‘Precision Medicine’ in asthma and allergy is arriving. As the field advances this may involve an individually tailored approach to the prevention, early detection, and treatment of disease based on the knowledge of an individual’s epigenetic profile.

Bisphenol A (BPA) is an estrogenic endocrine disruptor widely used in the production of plastics. Increasing evidence indicates that in utero BPA exposure affects sexual differentiation and behavior; however, the mechanisms underlying these effects are unknown. We hypothesized that BPA may disrupt epigenetic programming of gene expression in the brain. Here, we provide evidence that maternal exposure during pregnancy to environmentally relevant doses of BPA (2, 20, and 200 µg/kg/d) in mice induces sex-specific, dose-dependent (linear and curvilinear), and brain region-specific changes in expression of genes encoding estrogen receptors (ERs; ERα and ERβ) and estrogen-related receptor-γ in juvenile offspring. Concomitantly, BPA altered mRNA levels of epigenetic regulators DNA methyltransferase (DNMT) 1 and DNMT3A in the juvenile cortex and hypothalamus, paralleling changes in estrogen-related receptors. Importantly, changes in ERα and DNMT expression in the cortex (males) and hypothalamus (females) were associated with DNA methylation changes in the ERα gene. BPA exposure induced persistent, largely sex-specific effects on social and anxiety-like behavior, leading to disruption of sexually dimorphic behaviors. Although postnatal maternal care was altered in mothers treated with BPA during pregnancy, the effects of in utero BPA were not found to be mediated by maternal care. However, our data suggest that increased maternal care may partially attenuate the effects of in utero BPA on DNA methylation. Overall, we demonstrate that low-dose prenatal BPA exposure induces lasting epigenetic disruption in the brain that possibly underlie enduring effects of BPA on brain function and behavior, especially regarding sexually dimorphic phenotypes.

Background Bisphenol A (BPA) is used widely to manufacture food container linings. Mouse models suggest exposure to BPA might increase allergic inflammation. Objectives We hypothesized that BPA exposure, as assessed based on urinary BPA concentrations, would be associated with increased odds of wheeze and asthma and increased fraction of exhaled nitric oxide (Feno) values in children. Methods The Columbia Center for Children's Environmental Health recruited pregnant women for a prospective birth cohort study (n = 568). Mothers during the third trimester and children at ages 3, 5, and 7 years provided spot urine samples. Total urinary BPA concentrations were measured by using online solid-phase extraction, high-performance liquid chromatography, isotope-dilution tandem mass spectrometry. Wheeze in the last 12 months was measured by using questionnaires at ages 5, 6, and 7 years. Asthma was determined by a physician once between ages 5 and 12 years. Feno values were measured at ages 7 to 11 years. Results Prenatal urinary BPA concentrations were associated inversely with wheeze at age 5 years (odds ratio [OR], 0.7; 95% CI, 0.5-0.9; P = .02). Urinary BPA concentrations at age 3 years were associated positively with wheeze at ages 5 years (OR, 1.4; 95% CI, 1.1-1.8; P = .02) and 6 years (OR, 1.4; 95% CI, 1.0-1.9; P = .03). BPA concentrations at age 7 years were associated with wheeze at age 7 years (OR, 1.4; 95% CI, 1.0-1.9; P = .04) and Feno values (β = 0.1; 95% CI, 0.02-0.2; P = .02). BPA concentrations at ages 3, 5, and 7 years were associated with asthma (OR, 1.5 [95% CI, 1.1-2.0], P = .005; OR, 1.4 [95% CI, 1.0-1.9], P = .03; and OR, 1.5 [95% CI, 1.0-2.1], P = .04, respectively). Conclusions This is the first report of an association between postnatal urinary BPA concentrations and asthma in children.

Despite data associating exposure to traffic-related polycyclic aromatic hydrocarbons (PAH) in asthma, mechanistic support has been limited. We hypothesized that both prenatal and early postnatal exposure to PAH would increase airway hyperreactivity (AHR) and that the resulting AHR may be insensitive to treatment with a β 2AR agonist drug, procaterol. Further, we hypothesized that these exposures would be associated with altered β 2AR gene expression and DNA methylation in mouse lungs. Mice were exposed prenatally or postnatally to a nebulized PAH mixture versus negative control aerosol 5 days a week. Double knockout β 2AR mice were exposed postnatally only. Prenatal exposure to PAH was associated with reduced β 2AR gene expression among nonsensitized mice offspring, but not increases in DNA methylation or AHR. Postnatal exposure to PAH was borderline associated with increased AHR among sensitized wildtype, but not knockout mice. In the first study that delivers PAH aerosols to mice in a relatively physiological manner, small effects on AHR and β 2AR gene expression, but not β 2AR agonist drug activity, were observed. If confirmed, the results may suggest that exposure to PAH, common ambient urban pollutants, affects β 2AR function, although the impact on the efficacy of β 2AR agonist drugs used in treating asthma remains uncertain.

Study objective Laryngotracheal injury or edema in the setting of intubation may narrow the upper airway and predispose toward postextubation stridor. The presence or absence of an audible airleak when the sealing balloon cuff of the endotracheal tube is deflated has been demonstrated to be a marker of laryngotracheal edema in high-risk patients. We hypothesized that (1) the volume of the cuff leak can be quantified in a general medical ICU population, and (2) the cuff leak volume can be correlated with likelihood of postextubation stridor. Methods Within 24 h of both the initiation and termination of mechanical ventilation, the cuff leak volume, defined as the difference between the inspiratory tidal volume and the averaged expiratory tidal volume while the cuff around the endotracheal tube was deflated, was recorded. Results In 100 consecutive intubations, the preextubation cuff leak volume was 349±163 mL [mean± SD]). Overall, 6% of extubations were accompanied by postextubation stridor. The mean cuff leak volume measured within 24 h of planned extubation was significantly lower in those who subsequently developed stridor in comparison to those who did not (180±157 mL vs 360±157 mL; p=0.012). The positive predictive value for postextubation stridor in the setting of a cuff leak less than 110 mL was 0.80, the predictive value for absence of postextubation stridor with a cuff leak volume greater than 110 mL was 0.98, and the specificity of the test was 0.99. No other demographic factors or indexes related to mechanical ventilation were significantly different between the two groups. Conclusion A reduced cuff leak volume prior to extubation identifies a population at increased risk for postextubation stridor.

OBJECTIVE: Exercise-induced wheeze (EIW) may identify a distinct population among asthmatics and give insight into asthma morbidity etiology. The prevalence of pediatric asthma and associated urgent medical visits varies greatly by neighborhood in New York City and is highest in low-income neighborhoods. Although increased asthma severity might contribute to the disparities in urgent medical visits, when controlling for health insurance coverage, we previously observed no differences in clinical measures of severity between asthmatic children living in neighborhoods with lower (3%–9%) versus higher (11%–19%) asthma prevalence. Among these asthmatics, we hypothesized that EIW would be associated with urgent medical visits and a child’s neighborhood asthma prevalence. METHODS: Families of 7- to 8-year-old children were recruited into a case-control study of asthma through an employer-based health insurance provider. Among the asthmatics (n = 195), prevalence ratios (PRs) for EIW were estimated. Final models included children with valid measures of lung function, seroatopy, and waist circumference (n = 140). RESULTS: EIW was associated with urgent medical visits for asthma (PR, 2.29; P = .021), independent of frequent wheeze symptoms. In contrast to frequent wheeze, EIW was not associated with seroatopy or exhaled NO, suggesting a distinct mechanism. EIW prevalence among asthmatics increased with increasing neighborhood asthma prevalence (PR, 1.09; P = .012), after adjustment for race, ethnicity, maternal asthma, environmental tobacco smoke, household income, and neighborhood income. CONCLUSIONS: EIW may contribute to the disparities in urgent medical visits for asthma between high- and low-income neighborhoods. Physicians caring for asthmatics should consider EIW an indicator of risk for urgent medical visits.

Background: Outdoor ambient polycyclic aromatic hydrocarbon (PAH) concentrations are variable throughout an urban environment. However, little is known about how variation in semivolatile and nonvolatile PAHs related to the built environment (open space vs. semi-closed space) contributes to differences in concentrations. Methods: We simultaneously collected 14, two-week samples of PAHs from the outside of windows facing the front (adjacent to the street) open side of a New York City apartment building and the alley, semi-closed side of the same apartment unit between 2007 and 2012. We also analyzed samples of PAHs measured from 35 homes across Northern Manhattan and the Bronx, 17 from street facing windows with a median floor level of 4 (range 2–26) and 18 from alley-facing windows with a median floor level of 4 (range 1–15). Results: Levels of nonvolatile ambient PAHs were significantly higher when measured from a window adjacent to a street (an open space), compared to a window 30 feet away, adjacent to an alley (a semi-closed space) (street geometric mean (GM) 1.32 ng/m3, arithmetic mean ± standard deviation (AM ± SD) 1.61 ± 1.04 ng/m3; alley GM 1.10 ng/m3, AM ± SD 1.37 ± 0.94 ng/m3). In the neighborhood-wide comparison, nonvolatile PAHs were also significantly higher when measured adjacent to streets compared with adjacent to alley sides of apartment buildings (street GM 1.10 ng/m3, AM ± SD 1.46 ± 1.24 ng/m3; alley GM 0.61 ng/m3, AM ± SD 0.81 ± 0.80 ng/m3), but not semivolatile PAHs. Conclusions: Ambient PAHs, nonvolatile PAHs in particular, are significantly higher when measured from a window adjacent to a street compared to a window adjacent to an alley, despite both locations being relatively close to street traffic. This study highlights small-scale spatial variations in ambient PAH concentrations that may be related to the built environment (open space vs. semi-closed space) from which the samples are measured, as well as the relative distance from street traffic, that could impact accurate personal exposure assessments.

Background The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) reported that the inactivated influenza vaccine is safe for patients with asthma and recommended its use to reduce the morbidity associated with infection. Objective Because the ALA-ACRC's recommendation would include vaccination of all patients with asthma, including those with severe asthma and first-time vaccinees, we conducted a parallel study to address whether patients with asthma who report bronchospasm after vaccination might be demonstrating a hypersensitivity response to the vaccine. Methods Thirty-two adult patients with asthma from the ALA-ACRC cohort were recruited. Subjects were randomly assigned to receive influenza vaccine or placebo and then recorded asthma symptoms and peak expiratory flow rates for 14 days. On day 14, influenza vaccine and egg antigen–induced mononuclear cell proliferation and IFN-γ, IL-5, and IL-4 production were measured and compared with symptoms. Results Increased influenza but not egg antigen–induced mononuclear cell proliferation was present among vaccinated subjects. These responses were unrelated to asthma exacerbations after vaccine. There were no differences in cytokine production in response to either influenza or egg antigen in association with asthma exacerbations. Conclusions Episodes of bronchospasm after influenza vaccination do not seem related to hypersensitivity to the vaccine.

Despite considerable attention to the field of epigenetic regulation in the scientific literature and its heightened profile at scientific conferences and workshops, the unique connections between epigenetics and pediatric environmental health have not been given specific focus in public meetings. The Children’s Environmental Health Network (CEHN) convened a research conference, The Contribution of Epigenetics in Pediatric Environmental Health, on 30 May–1 June 2012 in San Francisco, California, to address this increasingly important research. CEHN is a national nonprofit organization celebrating 20 years of vital work to protect the developing child from environmental hazards by promoting safer and healthier environments (CEHN 2012). The conference successfully fostered collaborations across various scientific disciplines to further the understanding of the role of epigenetic regulation in pediatric environmental health, identified research gaps, and explored the relationship of pediatric environmental exposures with epigenetic regulation. The conference also laid the groundwork for translating research findings on epigenetic regulation important to pediatric health outcomes and informing the scientific and public health community about this rapidly growing field. Key leaders in pediatric and epigenetic research presented their work and actively participated in discussions (see abstracts online; CEHN Research Conference 2012). Much of the research focused on DNA methylation, an important mechanism of environmental influence on gene expression. The scientists addressed important research parameters, including critical windows of exposure, possible differences in epigenetic profiles between boys and girls, and changes in epigenetic markers as children age. Their research covered a range of environmental exposures associated with adverse health effects in children, including alcohol, bisphenol A (BPA), polycyclic aromatic hydrocarbons, arsenic, lead, organochlorines, polybrominated diphenyl ethers, secondhand smoke, and indoor allergens. Findings from a mix of animal and human subject studies generated stimulating discussions of how these exposures affect genes that code for inflammation, asthma, growth, obesity, cognitive development, hormone receptors, and tumor suppression, among others. Several researchers presented results from their work evaluating the role of nutrients such as choline and folate as modifiers of epigenetic changes with regard to specific environmental exposures such as alcohol or arsenic (CEHN Research Conference 2012). A total of 170 participants—scientists, health care workers, public policy advocates, and educators—participated in the conference. Young investigators were prominent, with 31 student and postdoctoral researchers in attendance. Three Junior Investigator Abstract Awards were presented for outstanding research in the areas of epigenetic effects of prenatal BPA exposure (Marija Kundakovic), DNA methylation and infant growth (Carolyn E. Banister), and epigenetic regulation after environmental intervention (Stephanie Lovinsky-Desir). The international research community was represented by colleagues from Malaysia, Italy, Brazil, India, the Netherlands, Canada, Australia, United Kingdom, South Africa, Austria, France, and China. Federal agencies were represented by participants from the U.S. Environmental Protection Agency, the National Institute of Environmental Health Sciences, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Media representatives from Epigenie, New Scientist, and Environmental Health Perspectives were also present.

Background 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. Methods 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). Results 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 p Foxp3: FSHS 74.60%, FnSHS 54.44%, p p IFN-γ: FSHS 0.75, FnSHS 1.52, p p Foxp3: FSHS 0.75, FnSHS 3.29, p p IFN-γ: FSHS vs. SSHS, p p Foxp3: FSHS vs. SSHS, p p IFN-γ: FSHS vs. SSHS, p p Foxp3: FSHS vs. SSHS, p p 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 Conclusions 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.

Background Exposure to traffic-related air pollutants, including polycyclic aromatic hydrocarbons (PAHs), can induce asthma. However, the effects of early repeated PAH exposure over time on different asthma phenotypes have not been examined. Objective To assess associations between repeated PAH exposure, measured from prenatal personal and residential indoor monitors in children's homes, and asthma in an inner-city cohort. Methods Prenatal exposure was assessed by personal air monitoring during 48 hours and exposure at 5 to 6 years of age by 2-week residential monitoring in the Columbia Center for Children's Environmental Health cohort. PAH was dichotomized into pyrene (representative semivolatile PAH) and the sum of 8 nonvolatile PAHs. High exposure to each was defined as measures above the median at both repeated time points. Asthma and wheeze were determined by validated questionnaires at ages 5 to 6 years. Children with specific IgE levels greater than 0.35 IU/mL to any of 5 indoor allergens were considered seroatopic. Results Among all 354 children, repeated high exposure to pyrene was associated with asthma (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.13-3.20). Among 242 nonatopic children, but not those sensitized to indoor allergens (n = 87) or with elevated total IgE levels (n = 171), high pyrene levels were associated positively with asthma (OR, 2.89; 95% CI, 1.77-5.69), asthma medication use (OR, 2.28; 95% CI, 1.13-4.59), and emergency department visits for asthma (OR, 2.43; 95% CI, 1.20-4.91). Associations between the levels of the 8 nonvolatile PAHs and asthma were not observed, even when stratifying by seroatopy. Conclusion Nonatopic children may be more susceptible to the respiratory consequences of early pyrene exposures.

Rationale: Previously we reported that airborne concentrations of cis-permethrin, but not trans-permethrin, measured during pregnancy in an inner city pediatric cohort was associated with cough by age 5. However, the effect of subsequent exposures to both permethrins during early childhood, and to piperonyl butoxide (PBO, a synergist for residential pyrethroid insecticides) remains to be elucidated. We hypothesized that prenatal and age 5–6 year measures of PBO and permethrins would be associated with cough at age 5–6 years in this cohort. Further, we explored the associations between these pesticide measures and wheeze, asthma, seroatopy, and fractional exhaled nitric oxide (FeNO). Methods: PBO and permethrins were measured in personal air during the third trimester of pregnancy and indoor residential air at age 5–6 years (n=224). Health outcome questionnaires were administered to the mothers of 5–6 year old children. Indoor allergen specific and total immunoglobulin (Ig) E production was measured from sera collected at age 5, and FeNO was measured at 5–6 years. The hypotheses were tested using regression models adjusting for common confounders. Results: Noninfectious cough was reported among 14% of children at age 5–6 years. Measures of prenatal PBO, but not age 5–6 year PBO or permethrins, increased the odds of cough [OR (95% CI): 1.27 (1.09–1.48), p

The biological mechanisms responsible for the onset and exacerbation of asthma symptoms in children may involve the epigenetic regulation of inflammatory genes after environmental exposures. Using buccal cells, we hypothesized that DNA methylation in promoter regions of two asthma genes, inducible nitric oxide synthase (iNOS) and interferon γ (IFNγ), can vary over several days. Repeat buccal samples were collected 4 to 7 days apart from 34 children participating in the Columbia Center for Children's Environmental Health (CCCEH) birth cohort study. Several field duplicates (sequential collection of two samples in the field) and replicates (one sample pyrosequenced twice) also were collected to ensure consistency with collection and laboratory procedures. DNA methylation was assessed by pyrosequencing a PCR of bisulfite-treated DNA. We found that replicate and field duplicate samples were correlated strongly (r = 0.86 to 0.99, P < 0.05), while repeat samples demonstrated low within-subject correlations (r = 0.19 to 0.56, P = 0.06 to 0.30). Our data reveal DNA methylation as a dynamic epigenetic mechanism that can be accessed safely and reproducibly in an inner city pediatric cohort using non-invasive buccal swabs and pyrosequencing technology.

T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.

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

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 PM(2.5) 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, R(2) = 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/mm(2). Furthermore, positive correlations (R(2) = 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.

Asthma is a disease that is influenced by environmental exposures, including those that occur prenatally. Recently, epigenetic regulation has been posited as an explanation for how environmental toxicants may induce asthma-related immune responses. However, our knowledge of the epigenetic regulation of asthma lags substantially behind our understanding of the epigenetic regulation of other complex diseases such as cancer. Fortunately new data are beginning to emerge. These include translational data from molecular experiments that implicate epigenetic regulation in T helper differentiation and/or the development of T regulatory cells, important in allergic immune responses. They also include a growing collection of cohort studies that associate epigenetic regulation with several components of the asthma clinical phenotype. So far these clinical studies are small, often unconfirmed, and only have started to address key issues relating to tissue specificity. Nonetheless, these studies provide a preview of what future research may reveal and raise the possibility that previously held paradigms for asthma pathogenesis may, and perhaps should, be changing.

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.

Background and Aims: In a cross-sectional study, butylbenzyl phthalate (BBzP) concentrations in house dust were associated with eczema and rhinitis among children ages 3-8 years. Our aim was to tes...

Background and Aims: Bisphenol-A (BPA), an endocrine disruptor widely used in food containers, has been associated with altered T regulatory and Th2 cytokine pathways. As these are critical for ast...

SOCS-1 is a critical regulator of multiple signaling pathways, including those activated by cytokines that regulate Ig H 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 compared with those of homozygotes for the G-allele. Analysis demonstrated that the SOCS1+1125G > C SNP was in complete linkage disequilibrium with an 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 decreased IgE. 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.