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RationaleAsthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset.ObjectivesTo determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association.MethodsWe studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years).Measurements and main resultsWe defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23).ConclusionsThis nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

Environmental exposures, psychosocial stressors and nutrition are all potentially important influences that may impact health outcomes directly or via interactions with the genome or epigenome over generations. While there have been clear successes in large-scale human genetic studies in recent decades, there is still a substantial amount of missing heritability to be elucidated for complex childhood disorders. Mounting evidence, primarily in animals, suggests environmental exposures may generate or perpetuate altered health outcomes across one or more generations. One putative mechanism for these environmental health effects is via altered epigenetic regulation. This review highlights the current epidemiologic literature and supporting animal studies that describe intergenerational and transgenerational health effects of environmental exposures. Both maternal and paternal exposures and transmission patterns are considered, with attention paid to the attendant ethical, legal and social implications.

Laura A Conrad,1 Natalie Buchinsky,2 Luis M Acosta,2 J David Nugent,3 Khalil W Savary,4 Rachel L Miller,5 Nurdant Emanet,6 Julie Herbstman,2 Beatrice Beebe,6 Michael M Myers,3 William P Fifer,3 Matthew S Perzanowski2 1Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, New York, NY, USA; 2Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA; 3Division of Developmental Neuroscience, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA; 4Department of Pediatrics, Rutgers University, Newark, NJ, USA; 5Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USACorrespondence: Matthew S PerzanowskiDepartment of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th St, 11th Floor, New York, NY, 10032, USATel +1 212-305-3465Fax +1 212-305-4012Email mp2217@cumc.columbia.eduIntroduction: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheeze, emergency department visits, and hospitalizations. These findings were independent of allergic sensitization, and we theorized that increased parasympathetic tone underlay the association. We also reported that increased heart-rate variability (HRV) in infants predicted wheeze in 2– 3 year-olds. In a convenience sample of children participating in a birth cohort study, we tested the hypothesis that infants with RWWC would have elevated HRV, indicating increased parasympathetic tone.Methods: RWWC symptoms since birth were queried for 3-month-old children. At 4-months, HRV was assessed (root mean square of successive differences [RMSSD]) during a standardized infant–mother still-face paradigm, which included 2 minutes

Environmental exposures, psychosocial stressors and nutrition are all potentially important influences that may impact health outcomes directly or via interactions with the genome or epigenome over generations. While there have been clear successes in large-scale human genetic studies in recent decades, there is still a substantial amount of missing heritability to be elucidated for complex childhood disorders. Mounting evidence, primarily in animals, suggests environmental exposures may generate or perpetuate altered health outcomes across one or more generations. One putative mechanism for these environmental health effects is via altered epigenetic regulation. This review highlights the current epidemiologic literature and supporting animal studies that describe intergenerational and transgenerational health effects of environmental exposures. Both maternal and paternal exposures and transmission patterns are considered, with attention paid to the attendant ethical, legal and social implications.

Laura A Conrad,1 Natalie Buchinsky,2 Luis M Acosta,2 J David Nugent,3 Khalil W Savary,4 Rachel L Miller,5 Nurdant Emanet,6 Julie Herbstman,2 Beatrice Beebe,6 Michael M Myers,3 William P Fifer,3 Matthew S Perzanowski2 1Division of Respiratory and Sleep Medicine, Albert Einstein College of Medicine, New York, NY, USA; 2Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA; 3Division of Developmental Neuroscience, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA; 4Department of Pediatrics, Rutgers University, Newark, NJ, USA; 5Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USACorrespondence: Matthew S PerzanowskiDepartment of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th St, 11th Floor, New York, NY, 10032, USATel +1 212-305-3465Fax +1 212-305-4012Email mp2217@cumc.columbia.eduIntroduction: Previously, we found that reported infant rhinorrhea and watery eyes without a cold (RWWC) predicted school age exercise-induced wheeze, emergency department visits, and hospitalizations. These findings were independent of allergic sensitization, and we theorized that increased parasympathetic tone underlay the association. We also reported that increased heart-rate variability (HRV) in infants predicted wheeze in 2– 3 year-olds. In a convenience sample of children participating in a birth cohort study, we tested the hypothesis that infants with RWWC would have elevated HRV, indicating increased parasympathetic tone.Methods: RWWC symptoms since birth were queried for 3-month-old children. At 4-months, HRV was assessed (root mean square of successive differences [RMSSD]) during a standardized infant–mother still-face paradigm, which included 2 minutes

BackgroundThe long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman's life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention.Main textDespite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland's structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals-including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols-and metals. We outline ways in which ongoing transdi

BackgroundThe long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman's life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention.Main textDespite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland's structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals-including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols-and metals. We outline ways in which ongoing transdi

Background:DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures. Results:Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030). Conclusions:Short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3.

Background:DNA methylation of CpG sites on genetic loci has been linked to increased risk of asthma in children exposed to elevated ambient air pollutants (AAPs). Further identification of specific CpG sites and the pollutants that are associated with methylation of these CpG sites in immune cells could impact our understanding of asthma pathophysiology. In this study, we sought to identify some CpG sites in specific genes that could be associated with asthma regulation (Foxp3 and IL10) and to identify the different AAPs for which exposure prior to the blood draw is linked to methylation levels at these sites. We recruited subjects from Fresno, California, an area known for high levels of AAPs. Blood samples and responses to questionnaires were obtained (n = 188), and in a subset of subjects (n = 33), repeat samples were collected 2 years later. Average measures of AAPs were obtained for 1, 15, 30, 90, 180, and 365 days prior to each blood draw to estimate the short-term vs. long-term effects of the AAP exposures. Results:Asthma was significantly associated with higher differentially methylated regions (DMRs) of the Foxp3 promoter region (p = 0.030) and the IL10 intronic region (p = 0.026). Additionally, at the 90-day time period (90 days prior to the blood draw), Foxp3 methylation was positively associated with NO2, CO, and PM2.5 exposures (p = 0.001, p = 0.001, and p = 0.012, respectively). In the subset of subjects retested 2 years later (n = 33), a positive association between AAP exposure and methylation was sustained. There was also a negative correlation between the average Foxp3 methylation of the promoter region and activated Treg levels (p = 0.039) and a positive correlation between the average IL10 methylation of region 3 of intron 4 and IL10 cytokine expression (p = 0.030). Conclusions:Short-term and long-term exposures to high levels of CO, NO2, and PM2.5 were associated with alterations in differentially methylated regions of Foxp3.

ObjectivesTo characterize patients who received tracheostomies for airway compromise or were initiated on long-term ventilation for chronic respiratory failure in PICUs and to examine variation in the incidence of initiation, patient characteristics, and modalities across sites.DesignRetrospective cross-sectional analysis.SettingsSeventy-three North American PICUs that participated in the Virtual Pediatric Systems, LLC.PatientsPICU patients admitted between 2009 and 2011.InterventionsNone.Measurements and main resultsAmong 115,437 PICU patients, 1.8% received a tracheostomy or were initiated on long-term ventilation; 1,034 received a tracheostomy only, 717 were initiated on invasive ventilation, and 381 were initiated on noninvasive ventilation. Ninety percent had substantial chronic conditions and comorbidities, including more than 50% with moderate or worse cerebral disability upon discharge. Seven percent were initiated after a catastrophic injury/event. Across sites, there was variation in incidence of tracheotomy and initiation of long-term ventilation, ranging from 0% to 4.6%. There also was variation in patient characteristics, time to tracheotomy, number of extubations prior to tracheostomy, and the use of invasive ventilation versus noninvasive ventilation.ConclusionsAlthough the PICU incidence of initiation of tracheostomies and long-term ventilation was relatively uncommon, it suggests that thousands of children and young adults receive these interventions each year in North American PICUs. The majority of them have conditions and comorbidities that impose on-going care needs, beyond those required by artificial airways and long-term ventilation themselves.

ObjectivesTo characterize patients who received tracheostomies for airway compromise or were initiated on long-term ventilation for chronic respiratory failure in PICUs and to examine variation in the incidence of initiation, patient characteristics, and modalities across sites.DesignRetrospective cross-sectional analysis.SettingsSeventy-three North American PICUs that participated in the Virtual Pediatric Systems, LLC.PatientsPICU patients admitted between 2009 and 2011.InterventionsNone.Measurements and main resultsAmong 115,437 PICU patients, 1.8% received a tracheostomy or were initiated on long-term ventilation; 1,034 received a tracheostomy only, 717 were initiated on invasive ventilation, and 381 were initiated on noninvasive ventilation. Ninety percent had substantial chronic conditions and comorbidities, including more than 50% with moderate or worse cerebral disability upon discharge. Seven percent were initiated after a catastrophic injury/event. Across sites, there was variation in incidence of tracheotomy and initiation of long-term ventilation, ranging from 0% to 4.6%. There also was variation in patient characteristics, time to tracheotomy, number of extubations prior to tracheostomy, and the use of invasive ventilation versus noninvasive ventilation.ConclusionsAlthough the PICU incidence of initiation of tracheostomies and long-term ventilation was relatively uncommon, it suggests that thousands of children and young adults receive these interventions each year in North American PICUs. The majority of them have conditions and comorbidities that impose on-going care needs, beyond those required by artificial airways and long-term ventilation themselves.

[Background]: Maternal asthma is a risk factor for asthma in offspring; however, transmission of the risk for allergic asthma without direct offspring sensitization has not been explored. [Objective]: To determine whether offspring from mothers with ovalbumin (OVA)-sensitized asthma would develop airway disease at first-ever exposure to OVA and whether preconception maternal treatment with the Antiasthma Simplified Herbal Medicine Intervention (ASHMI) or dexamethasone (DEX) could modify this risk in offspring [Methods]: Female BALB/c mice (F0) with OVA-induced asthma were generated using established protocols. Mice with asthma were treated with ASHMI, DEX, or water for 6 to 7 weeks. Naive mice served as controls. Subsequently, mice were mated. Twelve-day-old F1 offspring received 3 consecutive intranasal low- or high-dose OVA exposures without sensitization. Forty-eight hours later, airway inflammation, mucus hypersecretion, serum antibodies, and cytokines were evaluated. [Results]: Offspring from OVA-sensitized mothers, but not naive mothers, showed eosinophilic and neutrophilic airway inflammation, and mucus hyperplasia after OVA exposure and he presence of OVA-specific IgG1 and IgG2a. Offspring of ASHMI- and DEX-treated mothers showed decreased airway inflammation and mucus hypersecretion after low-dose OVA (P <.05-.001 for the 2 comparisons vs offspring of OVA/Sham mothers). Offspring of ASHMI-treated, but not DEX-treated, mothers were protected after the high-dose OVA challenge (P <.05-.01 vs offspring OVA/Sham). Maternal ASHMI therapy was associated with increased IgG2a (P <.01 vs offspring of OVA/Sham mothers) and decreased bronchoalveolar lavage fluid CXCL-1 and eotaxin-1 levels (P <.01 and P <.05, respectively, vs offspring of OVA/Sham mothers). [Conclusion]: Offspring of mothers with OVA-induced asthma developed airway inflammation and mucus to first-ever OVA exposure without prior sensitization. Maternal therapy with ASHMI was superior to DEX in decreasin

Atopic diseases are complex entities influenced by an array of risk factors including genetic predisposition, environmental allergens, antenatal exposures, infections and psychosocial factors. One proposed mechanism by which these risk factors contribute to the development of atopic disease is through alterations in the production of T helper type 1 (Th1) and type 2 (Th2) cytokines. The objectives of this review are to discuss antenatal exposures that are associated with pediatric atopic diseases, to discuss the influence of the intrauterine environment on neonatal immune responses, to provide an overview of the Th1 and Th2 pathways and how they relate to atopic disease, and to summarize our current understanding of the association between cytokine responses in cord blood and the development of atopic disease in early childhood.

Atopic diseases are complex entities influenced by an array of risk factors including genetic predisposition, environmental allergens, antenatal exposures, infections and psychosocial factors. One proposed mechanism by which these risk factors contribute to the development of atopic disease is through alterations in the production of T helper type 1 (Th1) and type 2 (Th2) cytokines. The objectives of this review are to discuss antenatal exposures that are associated with pediatric atopic diseases, to discuss the influence of the intrauterine environment on neonatal immune responses, to provide an overview of the Th1 and Th2 pathways and how they relate to atopic disease, and to summarize our current understanding of the association between cytokine responses in cord blood and the development of atopic disease in early childhood.