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Background: To investigate the intergenerational effects of grandmaternal smoking during pregnancy (GMSDP) on the DNA methylation of grandchildren. Methods: Data from the Isle of Wight birth cohort with information regarding GMSDP and DNA methylation profiling at the birth of grandchildren (n = 161) were used. Differentially methylated CpG sites related to GMSDP were identified using testing–training screening, analysis of variance and multivariate analysis of covariance. The association between identified CpG sites and expression levels of neighboring genes was tested by linear regression. Results: Twenty-three CpG sites were differentially methylated in grandchildren because of GMSDP, and eight of these were associated with expression levels of 13 neighboring genes. Conclusion: GMSDP has an intergenerational effect on the DNA methylation profile of grandchildren independent of maternal smoking during pregnancy.

Introduction Globally, the epidemiology of psoriasis is poorly understood, and most countries lack essential epidemiologic data regarding disease burden and its determinants. This study sought to estimate the prevalence of psoriasis among adolescents in Kuwait and assess its association with different risk factors, including obesity, sibship size, breastfeeding, and exposure to household secondhand smoke (SHS) and pets. Methods Schoolchildren aged 11–14 years (n = 3864) were enrolled in a cross-sectional study. Lifetime and current (past 12 months) prevalence of psoriasis were ascertained according to ever having a history of doctor-diagnosis plus current active lesion(s) and/or current use of treatment of psoriasis. Associations were assessed using Poisson regression with robust variance estimation, and adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated. Results The lifetime and current prevalence of psoriasis were estimated to be 3.6% (136/3806) and 1.1% (42/3806), respectively. Commonly reported anatomical sites affected by psoriasis included scalp (47.6%) and the extensor surface of the knees (50%) and elbows (38.1%). Household SHS exposure was associated with increased lifetime psoriasis (aPR = 1.41, 95% CI 1.07–1.98), and showed a trend for association with current psoriasis (1.77, 0.89–3.53). Similarly, cat-keeping during infancy was associated with lifetime psoriasis (1.96, 1.14–3.37), and demonstrated a trend for association with current psoriasis (1.49, 0.52–1.98). In contrast, breastfeeding was associated with a decreased lifetime psoriasis (0.62, 0.44–0.89), but was not associated with current psoriasis. Trend analyses showed that the prevalence of lifetime and current psoriasis increased with increasing numbers of total, older, and younger siblings. Conclusions Psoriasis affects a considerable proportion of schoolchildren in Kuwait. Interestingly, psoriasis prevalence was related to risk factors also found in allergic diseases, such as exposure to SHS, cat-keeping in infancy, breastfeeding, and sibship size, possibly suggesting a role of immune dysregulation.

Introduction: Assessments on whether prenatal antibiotic exposure and mode of delivery increase the risk of wheezing in infants and toddlers are inconsistent. Our goal is to evaluate the association between prenatal antibiotic use and Cesarean section with three subtypes of wheezing in infancy. Methods: An ongoing prospective three generations cohort study provides data on prenatal antibiotic use and mode of delivery. Respective questionnaire data was used to distinguish three subtypes of wheezing: any wheezing, infectious wheezing, and noninfectious wheezing. Repeated measurements of wheezing at 3, 6, and 12 months were analyzed using generalized estimation equations. Latent transition analysis assessed patterns of infant wheezing development in the first year of life. Results: The prevalence of any wheezing was highest at 12 months (40.1%). The prevalence of infectious wheezing was higher (3 months 23.8%, 6 months 33.5%, 12 months 38.5%) than of noninfectious wheezing (3 months 13.0%, 6 months 14.0%, 12 months 11.1%). About 11–13% of children had both infectious and noninfectious wheezing at 3, 6, and 12 months (3 months 10.7%, 6 months 13.9%, 12 months 13.1%). Children born via Cesarean section have approximately a 70–80% increase in the risk of any wheezing (RR = 1.83, 95% CI 1.29–2.60) and of infectious wheezing (RR = 1.72, 95% CI 1.18–2.50). Conclusions: Analyses of infectious and noninfectious wheezing subtypes suggests that children born by Cesarean sections may be more susceptible to infectious wheezing, warranting investigations into microbial factors of infectious wheezing. No significant associations were found between prenatal antibiotic exposure and wheezing types.

BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.

Background: Eczema is a common inflammatory skin disease with varying developmental trajectories/patterns that are influenced by different risk factors. The aim of this study was to investigate eczema development from infancy to early adulthood by identifying distinct developmental trajectories that describe disease patterns over time and evaluate the role of prenatal and early-life risk factors. Methods: The Isle of Wight Birth Cohort (n = 1456) was prospectively assessed at birth, 1, 2, 4, 10, 18 and 26 years. In all assessments, eczema was defined as chronic or chronically relapsing itchy dermatitis lasting >6 weeks with characteristic morphology and distribution in the past 12 months. Developmental trajectories of eczema between 1 or 2 and 26 years were identified separately for males and females by applying semiparametric mixture models. Associations were assessed by applying a modified Poisson regression to estimate adjusted risk ratios (aRR) and 95% confidence intervals (CI). Results: In both males and females, the following eczema developmental trajectories were identified: unaffected/transient (males: 77.7% vs. females: 73.0%), mid-onset late-resolving (males: 7.8% vs. females: 4.4%), late-onset (males: 5.2% vs. females: 9.5%) and early-onset persistent (males: 9.3% vs. females: 5.4%). In females, an additional trajectory was identified as follows: early-onset early-resolving (7.7%). Among males, filaggrin gene (FLG) variants (aRR = 2.45, 95% CI: 1.34–4.46) and paternal eczema (2.66, 1.39–5.08) were associated with the early-onset persistent trajectory. Among females, maternal eczema (2.84, 1.42–5.70) and high birthweight (2.25, 1.08–4.69) were associated with the early-onset persistent trajectory. Conclusions: Four and five trajectories represented eczema development among males and females, respectively, with different predisposing risk factors. Our results indicate that males and females may experience a different course of eczema.

Objectives: The role of children in the transmission of coronavirus disease 2019 (COVID-19) remains unclear. We investigated whether having children is associated with self-reported COVID-19 among adults. Subjects and Methods: A web-based cross-sectional study enrolled adults living in Kuwait (n = 2,355; aged ≥21 years). Prior COVID-19 diagnosis and having children were self-reported. Associations were assessed using Poisson regression, and adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) were estimated. Results: Of the 2,355 participants (1,595 female subjects), 744 (31.6%) and 605 (25.7%) were of age 21–29 and 30–39 years, respectively. Overall, 4.8% (114/2,355) of the participants reported having had COVID-19, with 4.8% of females and 5.1% of males reporting prior COVID-19 diagnosis. In the total study sample, having children showed a trend for association with having had COVID-19 (aPR: 1.46, 95% CI: 0.99–2.14, p = 0.056). Among participants aged 21–29 years, having children was associated with an increased prevalence of COVID-19 (aPR: 2.50, 95% CI: 1.21–5.20, p = 0.014). Such an association was not detected in adults aged ≥30 years. Conclusions: Our epidemiological findings highlight the possible role of children in spreading COVID-19. Hence, preventive measures should consider the role of children.

Due to climate change, bushfires are becoming a more frequent and more severe phenomenon which contributes to poor health effects associated with air pollution. In pregnancy, environmental exposures can have lifelong consequences for the fetus, but little is known about these consequences in the context of bushfire smoke exposure. In this review we summarise the current knowledge in this area, and propose a potential mechanism linking bushfire smoke exposure in utero to poor perinatal and respiratory outcomes in the offspring. Bushfire smoke exposure is associated with poor pregnancy outcomes including reduced birth weight and an increased risk of prematurity. Some publications have outlined the adverse health effects on young children, particularly in relation to emergency department presentations and hospital admissions for respiratory problems, but there are no studies in children who were exposed to bushfire smoke in utero. Prenatal stress is likely to occur as a result of catastrophic bushfire events, and stress is known to be associated with poor perinatal and respiratory outcomes. Changes to DNA methylation are potential epigenetic mechanisms linking both smoke particulate exposure and prenatal stress to poor childhood respiratory health outcomes. More research is needed in large pregnancy cohorts exposed to bushfire events to explore this further, and to design appropriate mitigation interventions, in this area of global public health importance.

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b+ DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C+, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo. Single cell RNA-sequencing (scRNA-Seq) of lung cDC2 indicates 5 distinct clusters. Pseudotime analysis of scRNA-Seq data and adoptive transfer experiments with purified cDC2 subpopulations suggest stepwise developmental progression of immature Ly-6C+Ly-6A/E+ cDC2 to mature Ly-6C–CD301b+ lung resident cDC2 lacking Ccr7 expression, which then further mature into CD200+ migratory cDC2 expressing Ccr7. Partially mature Ly-6C+Ly-6A/E–CD301b– cDC2, which express Il1b, promote Th17 differentiation. By contrast, CD200+ mature cDC2 strongly induce Th2, but not Th17, differentiation. Thus, Th17 and Th2 differentiation are promoted by lung cDC2 at distinct stages of maturation.

Background- While the majority of asthma starts in early childhood, asthma onset in some individuals occurs during adolescence or in adulthood. However, the pathogenesis of later onset asthma as well as the observed sex specificity are not well understood. Objective- We hypothesized that DNAm at specific CpG sites measured before disease onset, either in pre- or post-adolescence would be associated with asthma acquisition both during adolescence and in later adulthood. Methods- Subjects from the Isle of Wight Birth Cohort (IOWBC) were included. DNAm in blood at ages 10 (pre-adolescence) and 18 (post-adolescence), and asthma acquisition from age 10-18, and 18-26 years was studied. To improve statistical power, we first screened epigenome-wide CpGs based on the association of DNAm at 10 years with asthma acquisition from 10-18 years. Logistic regression with repeated measures were then applied to the CpGs that survived screening to examine the associations of pre-adolescence DNAm with asthma acquisition from pre-to post-adolescence, and post-adolescence DNAm with asthma acquisition from post-adolescence to adulthood. The effect of DNAm on asthma acquisition at different transition period was evaluated using interaction terms. The ALSPAC birth cohort was used for independent replication. For biological assessment of identified CpGs, pathway enrichment analysis and Differentially Methylated Regions were assessed. Results- Significant interaction effects of DNAm and transition period (10-18 or 18-26 years) on asthma acquisition were found for 17 CpGs in males and 98 CpGs in females (FDR=0.05) in IOWBC. Consistent interaction effects were observed for 9 CpGs in males and 53 CpGs in females in ALSPAC. For CpGs not showing interaction effects (i.e., effect of DNAm is stable over time), association with asthma acquisition was found for 38 CpGs in males and 52 CpGs in females in IOWBC. Of these 90 CpGs, at 13 CpG in males and 37 CpG in females, consistent direction of associations was observed in ALSPAC. Genes that the identified CpGs were mapped to, e.g., AKAP1 and ENO1, have shown to be associated with asthma. Conclusion- DNAm at specific CpGs is associated with asthma acquisition and such association is likely to be sex and transition period specific.

DNA methylation (DNAm) in blood (umbilical cord blood and capillary blood collected after birth on Guthrie cards) during the perinatal period is being increasingly studied with the aim of identifying epigenetic markers of in utero environmental exposures or later disease development. However, the comparability in DNAm between these two sources is unknown. To this end, DNAm from the cord blood and capillary blood of 34 subjects in the Isle of Wight 3rd Generation Birth Cohort (68 samples) were included to assess the comparability. Differences in average DNAm (overall agreement), correlations in DNAm, and intra-class correlation coefficients (ICC) in DNAm between the two sources, at each of the 430,742 CpG sites, were evaluated. The results showed that a high proportion (70.1%) of the CpGs DNAm agreed between cord blood and neonatal blood on Guthrie cards. A small portion of CpGs showed high correlation (correlation ≥0.5) or high ICC (ICC ≥0.5) in DNAm of the whole genome. This proportion increased dramatically in differentially methylated regions (DMRs) that are associated with exposure to maternal smoking, between the two sources.

The CD4Cre transgenic model has been widely used for T cell–specific gene manipulation. We report unexpected highly efficient Cre-mediated recombination in alveolar macrophages (AMFs), bronchial epithelial cells (BECs), and alveolar epithelial cells (AECs) in this strain of mice. Different from CD4 T cells, AMFs, AECs, and BECs do not express detectable Cre protein, suggesting that Cre protein is either very transiently expressed in these cells or only expressed in their precursors. Mice carrying a conditional constitutively active KRas (caKRas) allele and the CD4Cre transgene contain not only hyperactivated T cells but also develop severe AMF accumulation, AEC and BEC hyperplasia, and adenomas in the lung, leading to early lethality correlated with caKRas expression in these cells. We propose that caKRas–CD4Cre mice represent, to our knowledge, a novel model of proliferative pneumonitis involving macrophages and epithelial cells and that the CD4Cre model may offer unique usefulness for studying gene functions simultaneously in multilineages in the lung. Our observations, additionally, suggest that caution in data interpretation is warranted when using the CD4Cre transgenic model for T cell–specific gene manipulation, particularly when lung pathophysiological status is being examined.

Background: To identify novel epigenetic markers of adolescent asthma and replicate findings in an independent cohort, then explore whether such markers are detectable at birth, predictive of early-life wheeze, and associated with gene expression in cord blood.Methods: We performed epigenome-wide screening with recursive random forest feature selection and internal validation in the IOW birth cohort. We then tested whether we could replicate these findings in the independent cohort ALSPAC andfollowed-up our top finding with children of the IOW cohort. Results: We identified 10 CpG sites associated with adolescent asthma at a 5% false discovery rate (IOW, n=370), five of which exhibited evidence of associations in the replication study (ALSPAC, n=720). One site, cg16658191, within HK1 displayed particularly strong associations after cellular heterogeneity adjustments in both cohorts (OR-IOW = 0.17, 95% CI = 0.04-0.57) (OR-ALSPAC = 0.57, 95% CI = 0.38-0.87).Additionally, higher expression of HK1 (OR = 3.81, 95% CI = 1.41-11.77) in cord bloodwas predictive of wheezing in infancy (n=82).Conclusion: We identified novel associations between asthma and wheeze with methylation at cg16658191 and the expression of HK1, which may serve as markers of, predictors of, and potentially etiologic factors involved in asthma and early life wheeze.

Purpose Body mass index (BMI) is associated with asthma but associations of BMI temporal patterns with asthma incidence are unclear. Previous studies suggest that DNA methylation (DNAm) is associated with asthma status and variation in DNAm is a consequence of BMI changes. This study assessed the direct and indirect (via DNAm) effects of BMI trajectories in childhood on asthma incidence at young adulthood. Methods Data from the Isle of Wight (IoW) birth cohort were included in the analyses. Group-based trajectory modelling was applied to infer latent BMI trajectories from ages 1 to 10 years. An R package, ttscreening, was applied to identify differentially methylated CpGs at age 10 years associated with BMI trajectories, stratified for sex. Logistic regressions were used to further exclude CpGs with DNAm at age 10 years not associated with asthma incidence at 18 years. CpGs discovered via path analyses that mediated the association of BMI trajectories with asthma incidence in the IoW cohort were further tested in an independent cohort, the Avon Longitudinal Study of Children and Parents (ALSPAC). Results Two BMI trajectories (high vs. normal) were identified. Of the 442,474 CpG sites, DNAm at 159 CpGs in males and 212 in females were potentially associated with BMI trajectories. Assessment of their association with asthma incidence identified 9 CpGs in males and 6 CpGs in females. DNAm at 4 of these 15 CpGs showed statistically significant mediation effects (p-value Conclusion The association of BMI trajectory in childhood with asthma incidence at young adulthood is possibly mediated by DNAm.

Air pollution exposure during pregnancy may be a risk factor for altered immune maturation in the offspring. We investigated the association between ambient air pollutants during pregnancy and cell populations in cord blood from babies born to mothers with asthma enrolled in the Breathing for Life Trial. For each patient (n = 91), daily mean ambient air pollutant levels were extracted during their entire pregnancy for sulfur dioxide (SO2), nitric oxide, nitrogen dioxide, carbon monoxide, ozone, particulate matter &lt, 10 μm (PM10) or &lt, 2.5 μm (PM2.5), humidity, and temperature. Ninety-one cord blood samples were collected, stained, and assessed using fluorescence-activated cell sorting (FACS). Principal Component (PC) analyses of both air pollutants and cell types with linear regression were employed to define associations. Considering risk factors and correlations between PCs, only one PC from air pollutants and two from cell types were statistically significant. PCs from air pollutants were characterized by higher PM2.5 and lower SO2 levels. PCs from cell types were characterized by high numbers of CD8 T cells, low numbers of CD4 T cells, and by high numbers of plasmacytoid dendritic cells (pDC) and low numbers of myeloid DCs (mDCs). PM2.5 levels during pregnancy were significantly associated with high numbers of pDCs (p = 0.006), and SO2 with high numbers of CD8 T cells (p = 0.002) and low numbers of CD4 T cells (p = 0.011) and mDCs (p = 4.43 × 10−6) in cord blood. These data suggest that ambient SO2 and PM2.5 exposure are associated with shifts in cord blood cell types that are known to play significant roles in inflammatory respiratory disease in childhood.

Fetal exposure to tobacco smoke is an adverse risk factor for newborns. A plausible mechanism of how this exposure may negatively impact long term health is differential methylation of deoxyribonucleic acid (DNAm) and its relation to birth weight. We examined whether self-reported gestational smoking status and maternal exhaled carbon monoxide (eCO) during early pregnancy were associated with methylation of cytosine by guanines (CpG) sites that themselves predicted birth weight. We focused first on CpGs associated with maternal smoking, and secondly, among these, on CpGs related to birth weight found in another cohort. Then in 94 newborns from the Breathing for Life Trial (BLT) DNAm levels in cord blood were determined using Infinium Methylation EPIC BeadChip measuring &gt, 850K CpGs. We regressed CpGs on eCO and tested via mediation analysis whether CpGs link eCO to birth weight. Nine smoking related CpG sites were significantly associated with birth weight. Among these nine CpGs the methylation of cg02264407 on the LMO7 gene was statistically significant and linked with eCO measurements. eCO greater than six ppm showed a 2.3% decrease in infant DNAm (p = 0.035) on the LMO7 gene. A 1% decrease in methylation at this site resulted in decreased birth weight by 44.8 g (p = 0.003). None of the nine CpGs tested was associated with self-reported smoking. This is the first study to report potential mediation of DNA methylation, linking eCO measurements during early pregnancy with birth weight.

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P −7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10−4; adolescence Penrichment = 2.10 × 10−7). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

Aims: Bisphenol A (BPA)-based dental composites have commonly been used to fill dental cavities or seal pits and fissures on teeth. However, epidemiological evidence with regard to the BPA exposure from dental composites among children has rarely been reported. This study investigated whether there is a relationship between the BPA concentration in urine and the presence of composite restorations and sealants among South Korean children. Methods: Oral examinations and urine sample analyses were conducted on a total of 495 children aged 8–9 years. We classified the participants into four groups by the number of resin composites and sealant surfaces (0, 1–5, 6–10 and 11+). Results: BPA concentrations in urine were higher in children with 11 or more surfaces restored with sealants and resin composites than in those with zero restored surfaces, although no difference was seen in the group with 1–10 surfaces. After adjusting for gender and age, the urinary BPA concentration in children with 11 or more resin composite surfaces was 2.67 lg ⁄ g creatinine, which was higher than the concentration found in those with no filling surfaces ( P< 0.01). Conclusions: Having many dental composite filling surfaces on teeth may increase the urinary BPA concentration in children.

Objective Offspring born to mothers with asthma in pregnancy are known to have lower lung function which tracks with age. Human group 2 innate lymphoid cells (ILC2) accumulate in foetal lungs, at 10‐fold higher levels compared to adult lungs. However, there are no data on foetal ILC2 numbers and the association with respiratory health outcomes such as lung function in early life. We aimed to investigate cord blood immune cell populations from babies born to mothers with asthma in pregnancy. Methods Cord blood from babies born to asthmatic mothers was collected, and cells were stained in whole cord blood. Analyses were done using traditional gating approaches and computational methodologies (t‐distributed stochastic neighbour embedding and PhenoGraph algorithms). At 6 weeks of age, the time to peak tidal expiratory flow as a percentage of total expiratory flow time (tPTEF/tE%) was determined as well as Lung Clearance Index (LCI), during quiet natural sleep. Results Of 110 eligible infants (March 2017 to November 2019), 91 were successfully immunophenotyped (82.7%). Lung function was attempted in 61 infants (67.0%), and 43 of those infants (70.5% of attempted) had technically acceptable tPTEF/tE% measurements. Thirty‐four infants (55.7% of attempted) had acceptable LCI measurements. Foetal ILC2 numbers with increased expression of chemoattractant receptor‐homologous molecule (CRTh2), characterised by two distinct analysis methodologies, were associated with poorer infant lung function at 6 weeks of age.” Conclusion Foetal immune responses may be a surrogate variable for or directly influence lung function outcomes in early life., Cord blood CRTh2high ILC2 populations from infants born to asthmatic mothers may influence lung function later in life. The association between cord blood CRTh2high ILC2 and foetal eosinophils numbers may indicate a role of foetal ILC2 in promoting eosinophilia, which warrants further investigation.

The acquisition of antibiotic resistance (AR) by foodborne pathogens, such as Salmonella enterica, has emerged as a serious public health concern. The relationship between the two key survival mechanisms (i.e., antibiotic resistance and virulence) of bacterial pathogens is complex. However, it is unclear if the presence of certain virulence determinants (i.e., virulence genes) and AR have any association in Salmonella. In this study, we report the prevalence of selected virulence genes and their association with AR in a set of phenotypically tested antibiotic-resistant (n = 117) and antibiotic-susceptible (n = 94) clinical isolates of Salmonella collected from Tennessee, USA. Profiling of virulence genes (i.e., virulotyping) in Salmonella isolates (n = 211) was conducted by targeting 13 known virulence genes and a gene for class 1 integron. The association of the presence/absence of virulence genes in an isolate with their AR phenotypes was determined by the machine learning algorithm Random Forest. The analysis revealed that Salmonella virulotypes with gene clusters consisting of avrA, gipA, sodC1, and sopE1 were strongly associated with any resistant phenotypes. To conclude, the results of this exploratory study shed light on the association of specific virulence genes with drug-resistant phenotypes of Salmonella. The presence of certain virulence genes clusters in resistant isolates may become useful for the risk assessment and management of salmonellosis caused by drug-resistant Salmonella in humans.

This study aims to evaluate the association of maternal DNA methylation (DNAm) during pregnancy and offspring birthweight. One hundred twenty-two newborn-mother dyads from the Isle of Wight (IOW) cohort were studied to identify differentially methylated cytosine-phosphate-guanine sites (CpGs) in maternal blood associated with offspring birthweight. Peripheral blood samples were drawn from mothers at 22–38 weeks of pregnancy for epigenome-wide DNAm assessment using the Illumina Infinium HumanMethylation450K array. Candidate CpGs were identified using a course of 100 repetitions of a training and testing process with robust regressions. CpGs were considered informative if they showed statistical significance in at least 80% of training and testing samples. Linear mixed models adjusting for covariates were applied to further assess the selected CpGs. The Swedish Born Into Life cohort was used to replicate our findings (n = 33). Eight candidate CpGs corresponding to the genes LMF1, KIF9, KLHL18, DAB1, VAX2, CD207, SCT, SCYL2, DEPDC4, NECAP1, and SFRS3 in mothers were identified as statistically significantly associated with their children’s birthweight in the IOW cohort and confirmed by linear mixed models after adjusting for covariates. Of these, in the replication cohort, three CpGs (cg01816814, cg23153661, and cg17722033 with p values = 0.06, 0.175, and 0.166, respectively) associated with four genes (LMF1, VAX2, CD207, and NECAP1) were marginally significant. Biological pathway analyses of three of the genes revealed cellular processes such as endocytosis (possibly sustaining an adequate maternal-fetal interface) and metabolic processes such as regulation of lipoprotein lipase activity (involved in providing substrates for the developing fetus). Our results contribute to an epigenetic understanding of maternal involvement in offspring birthweight. Measuring DNAm levels of maternal CpGs may in the future serve as a diagnostic tool recognizing mothers at risk for pregnancies ending with altered birthweights.

BACKGROUND Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing subsequent asthma. Maternal asthma might also increase this risk. The aim of this study was to investigate the combined effects of hospitalization for RV positive bronchiolitis in infancy and a history of maternal asthma on the development of asthma at preschool age. METHODS This is a prospective cohort study of 139 preschool-aged children, with a history of hospital admission for bronchiolitis in infancy, followed-up to ascertain asthma and asthma-like symptoms, skin prick allergy test positivity, and lung function measured pre- and post-bronchodilator using impulse oscillometry. RESULTS Children with a past hospitalization for RV positive bronchiolitis (42.4% of all) and a history of maternal asthma (36.7% of all) had the greatest prevalence and risk ratio (RR) for doctor-diagnosed asthma (prevalence 81.8% and RR 2.10, 95% confidence interval [CI] 1.37-3.19, p = .001), use of inhaled corticosteroids (68.2% and RR 2.17, 95% CI 1.19-3.99, p = .001) and short-acting β-agonists in the last 12 months (95.2% and RR 1.49, 95% CI 1.17-1.89, p = .001), as compared to those with RV negative bronchiolitis and no maternal asthma history. More children in this group had an abnormal airway resistance (33.3% and adjusted risk ratio [aRR] 3.11, 95% CI 1.03-9.47, p = .045) and reactance (27.8% and aRR 2.11, 95% CI 1.06-4.26, p = .035) at 5 Hz, as compared to those with RV negative bronchiolitis and no maternal asthma history. CONCLUSION Hospitalization for RV positive bronchiolitis in early life combined with a history of maternal asthma identifies a subgroup of children with a high asthma burden while participants with only one of the two risk factors had intermediate risk for asthma.

BackgroundUnderlying biological mechanisms involved in sex differences in asthma status changes from pre‐ to post‐adolescence are unclear. DNA methylation (DNAm) has been shown to be associated with the risk of asthma.ObjectiveWe hypothesized that asthma acquisition from pre‐ to post‐adolescence was associated with changes in DNAm during this period at asthma‐associated cytosine‐phosphate‐guanine (CpG) sites and such an association was sex‐specific.MethodsSubjects from the Isle of Wight birth cohort (IOWBC) with DNAm in blood at ages 10 and 18 years (n = 124 females, 151 males) were studied. Using a training‐testing approach, epigenome‐wide CpGs associated with asthma were identified. Logistic regression was used to examine sex‐specific associations of DNAm changes with asthma acquisition between ages 10 and 18 at asthma‐associated CpGs. The ALSPAC birth cohort was used for independent replication. To assess functional relevance of identified CpGs, association of DNAm with gene expression in blood was assessed.ResultsWe identified 535 CpGs potentially associated with asthma. Significant interaction effects of DNAm changes and sex on asthma acquisition in adolescence were found at 13 of the 535 CpGs in IOWBC (P‐values IFRD1 linked to asthma, shows strong sex‐specific effects on asthma transition (P‐values Conclusion and clinical relevanceGender reversal in asthma acquisition is associated with opposite changes in DNAm (males vs females) from pre‐ to post‐adolescence at asthma‐associated CpGs. These CpGs are potential biomarkers of sex‐specific asthma acquisition in adolescence.

The cause and underlying mechanisms that contribute to asthma pathogenesis are not well known. Both genome- and epigenome-wide association studies have identified genes associated with asthma risk. It is unknown to what extent genes identified in these two types of studies overlap. Based on existing literature and the DisGeNET database, we extracted overlapping genes identified in genetic and epigenetic studies of childhood asthma. Through analyses of variance, we assessed whether DNA methylation (DNAm) at 5′-C-phosphate-G-3′ (CpGs) on the overlapping genes was associated with neighboring single-nucleotide polymorphisms (SNPs) within 1M base pairs (bps) and with low linkage disequilibrium (r 2 < 0.2) in the childhood asthma-related genes. In total, 285 genes from genetic studies and 226 genes from epigenetic studies were shown to be associated with asthma risk, of which six overlap. Of the six genes, 79 CpGs and 8229 unique neighboring SNPs (1M bps) were included in methylation quantitative loci (methQTL) assessment analyses. We tested the association of DNAm at each of the 79 CpG sites with its neighboring SNPs. After adjusting for multiple testing by controlling the false discovery rate to 0.05 when testing methQTL for each CpG site, we found statistically significant associations in three genes with their neighboring SNPs and identified 34 unique methQTLs. The rather limited overlap in genes between genetic and epigenetic studies on asthma and the absence of methQTL in some of the overlapping genes highlight a need to jointly, rather than independently, examine genetic and epigenetic effects on asthma risk to improve our understanding of the underlying mechanisms of asthma.

Several small studies have shown associations between breastfeeding and genome-wide DNA methylation (DNAm). We performed a comprehensive Epigenome-Wide Association Study (EWAS) to identify associations between breastfeeding and DNAm patterns in childhood. We analysed DNAm data from the Isle of Wight Birth Cohort at birth, 10, 18 and 26 years. The feeding method was categorized as breastfeeding duration &gt, 3 months and &gt, 6 months, and exclusive breastfeeding duration &gt, 3 months. EWASs using robust linear regression were performed to identify differentially methylated positions (DMPs) in breastfed and non-breastfed children at age 10 (false discovery rate of 5%). Differentially methylated regions (DMRs) were identified using comb-p. The persistence of significant associations was evaluated in neonates and individuals at 18 and 26 years. Two DMPs, in genes SNX25 and LINC00840, were significantly associated with breastfeeding duration &gt, 6 months at 10 years and was replicated for &gt, 3 months of exclusive breastfeeding. Additionally, a significant DMR spanning the gene FDFT1 was identified in 10-year-old children who were exposed to a breastfeeding duration &gt, 3 months. None of these signals persisted to 18 or 26 years. This study lends further support for a suggestive role of DNAm in the known benefits of breastfeeding on a child&rsquo, s future health.

Dendritic cells orchestrate the crosstalk between innate and adaptive immunity. CD8α+ dendritic cells present antigens to CD8+ T cells and elicit cytotoxic T cell responses to viruses, bacteria and tumours 1 . Although lineage-specific transcriptional regulators of CD8α+ dendritic cell development have been identified 2 , the molecular pathways that selectively orchestrate CD8α+ dendritic cell function remain elusive. Moreover, metabolic reprogramming is important for dendritic cell development and activation3,4, but metabolic dependence and regulation of dendritic cell subsets are largely uncharacterized. Here we use a data-driven systems biology algorithm (NetBID) to identify a role of the Hippo pathway kinases Mst1 and Mst2 (Mst1/2) in selectively programming CD8α+ dendritic cell function and metabolism. Our NetBID analysis reveals a marked enrichment of the activities of Hippo pathway kinases in CD8α+ dendritic cells relative to CD8α− dendritic cells. Dendritic cell-specific deletion of Mst1/2—but not Lats1 and Lats2 (Lats1/2) or Yap and Taz (Yap/Taz), which mediate canonical Hippo signalling—disrupts homeostasis and function of CD8+ T cells and anti-tumour immunity. Mst1/2-deficient CD8α+ dendritic cells are impaired in presentation of extracellular proteins and cognate peptides to prime CD8+ T cells, while CD8α− dendritic cells that lack Mst1/2 have largely normal function. Mechanistically, compared to CD8α− dendritic cells, CD8α+ dendritic cells exhibit much stronger oxidative metabolism and critically depend on Mst1/2 signalling to maintain bioenergetic activities and mitochondrial dynamics for their functional capacities. Further, selective expression of IL-12 by CD8α+ dendritic cells depends on Mst1/2 and the crosstalk with non-canonical NF-κB signalling. Our findings identify Mst1/2 as selective drivers of CD8α+ dendritic cell function by integrating metabolic activity and cytokine signalling, and highlight that the interplay between immune signalling and metabolic reprogramming underlies the unique functions of dendritic cell subsets. A data-driven analysis helps to identify specific roles of the Hippo signalling kinases Mst1 and Mst2 in integrating metabolic activity and cytokine signalling in dendritic cells, and thereby orchestrating immune cell function.

BACKGROUND: It is unclear whether inhaled corticosteroids (ICS) have chemopreventive effect on lung cancer (LC) development in humans. We investigated the association between the ICS use in asthma patients and the risk of LC. METHODS: We conducted a nationwide, population-based retrospective cohort study using the National Health Insurance database. We identified 4210 asthmatics who were initially free of LC and regularly used ICS between 2001 and 2005 and 37,228 asthmatics without regular ICS use. Patients with documented history of tobacco use were excluded from the analyses. Asthmatics were categorized into a mild and a severe asthma group. Each patient was tracked until the end of 2010 to identify incident cases of LC. Cox proportional hazards models were used to evaluate the effect of ICS on the risk of LC, further stratifying by asthma severity and comorbidities. RESULTS: During follow-up, we identified 747 incident cases of LC diagnosed in the asthma cohort. Compared with severe asthmatics without regular ICS use, the risk of LC for those with mild asthma with regular ICS use was lower (adjusted hazard ratio = 0.42, 95% confidence interval = 0.31–0.56, P < 0.0001). The risk of LC was calculated among the following rankings of risk severe asthma without regular ICS use, low severity without regular ICS, high severity with regular ICS, and low severity with regular ICS group showed a decreasing trend of LC incidence (P = 0.041). Analyses stratified by comorbidities revealed that the protective effect of ICS was assessed with better precision and more pronounced in those with renal diseases, stroke, and hyperlipidemia. CONCLUSIONS: For patients with asthma, regular ICS use might have a protective effect against LC. Further studies are required to assess this potential association from both immunohistopathological and clinical aspects.

Karmaus et al. show that loss of mechanistic target of rapamycin complex 1 (mTORC1) signaling impairs myelopoiesis. M-CSF–dependent myelopoiesis requires mTORC1 signaling and anabolic metabolism, which in turn promote expression of M-CSFR and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis., Myelopoiesis is necessary for the generation of mature myeloid cells during homeostatic turnover and immunological insults; however, the metabolic requirements for this process remain poorly defined. Here, we demonstrate that myelopoiesis, including monocyte and macrophage differentiation, requires mechanistic target of rapamycin complex 1 (mTORC1) signaling and anabolic metabolism. Loss of mTORC1 impaired myelopoiesis under steady state and dampened innate immune responses against Listeria monocytogenes infection. Stimulation of hematopoietic progenitors with macrophage colony-stimulating factor (M-CSF) resulted in mTORC1-dependent anabolic metabolism, which in turn promoted expression of M-CSF receptor and transcription factors PU.1 and IRF8, thereby constituting a feed-forward loop for myelopoiesis. Mechanistically, mTORC1 engaged glucose metabolism and initiated a transcriptional program involving Myc activation and sterol biosynthesis after M-CSF stimulation. Perturbation of glucose metabolism or disruption of Myc function or sterol biosynthesis impaired myeloid differentiation. Integrative metabolomic and genomic profiling further identified one-carbon metabolism as a central node in mTORC1-dependent myelopoiesis. Therefore, the interplay between mTORC1 signaling and metabolic reprogramming underlies M-CSF–induced myelopoiesis.

Polycyclic aromatic hydrocarbons (PAHs) are known for their carcinogenic and teratogenic properties. However, little is known about the effect of PAH on our immune and respiratory systems. Hence, we investigated associations (1) between PAH exposure and IgE levels and asthma in children and (2) between PAH exposure and the oxidative stress marker 8OHdG potentially involved in disease pathogenesis stratifying by (3) sex-based differences. A total of 453 kindergarten children were recruited and provided samples. Urine biomarker of PAH exposure (1-OHP levels) was measured by UPLC-MS/MS and a marker of oxidative stress (8OHdG) was measured by ELISA. Serum IgE were assessed and information on asthma was collected. Associations between 1-OHP levels, 8OHdG, IgE and asthma were analyzed by multivariate linear and logistic regression. A mediation analysis was conducted to evaluate whether the risk of increased IgE and asthma related to PAH exposure is explained by 8OHdG changes. Urine 1-OHP levels were positively related to 8OHdG levels (per ln-unit: β = 0.30kU/l, p = 0.002). Similar results were also found for 1-OHP levels with IgE levels (per ln-unit: β = 0.27 kU/l, p = 0.027). 1-OHP levels (per ln-unit) were significantly associated with asthma, with an OR (95% CI) of 1.42 (1.18–1.70). In addition, 1-OHP levels were associated with asthma. It is estimated that 35% of the effect of PAH exposure on asthma is mediated by 8OHdG levels. Exposure to PAH may enhance oxidative stress and may induce asthma. The effect of PAH exposure on asthma may be mediated by oxidative stress.

STUDY QUESTIONIs the age of onset of pubertal markers related to subsequent changes in DNA methylation (DNAm)?SUMMARY ANSWERWe identified 273 cytosine-phosphate-guanine (CpG) dinucleotides in girls and 67 CpGs in boys that were related to puberty and that were replicable in two other investigations.WHAT IS KNOWN ALREADYPreviously, 457 CpGs (not gender-specific) and 347 (in girls) and 50 (in boys), respectively, were found to be associated with puberty, according to investigations of studies from Denmark (20 girls and 31 boys) and North America (30 girls and 25 boys).STUDY DESIGN, SIZE, DURATIONThe study was based on a birth cohort of 1456 participants born in 1989/90, with follow-up at age 10 and 18 years.PARTICIPANTS/MATERIALS, SETTING, METHODSThe follow-up included 470 participants with information on DNAm and age of pubertal onset (244 girls and 226 boys). Age of pubertal onset was ascertained retrospectively at age 18 years. Using the Pubertal Development Scale, both genders were asked about ages of onset of growth spurt, body hair growth and skin changes. Ages at voice deepening and growth of facial hair were inquired from boys; ages at breast development and menarche from girls. Blood samples were collected at 10 and 18 years of age. DNA was extracted using a standard salting out procedure. The methylation level for each CpG site was assessed using one of two different platforms. DNAm was measured by a ratio of intensities denoted as β values for each CpG site. After quality control, 349 455 CpG sites were available for analysis. M values were calculated (log2(β/(1−β)) to approximate a normal distribution, and their levels were adjusted for blood cell proportions. Linear mixed models were applied to test the association between age of pubertal markers and repeated measurement of DNAm at 10 and 18 years.MAIN RESULTS AND THE ROLE OF CHANCEIn girls, a total of 63 019 CpGs statistically significantly changed after occurrence of any of the five pubertal events and 13 487 were changed subsequent to all five events: the respective number is boys were 3072 and 301. To further exclude false-positive findings, we investigated which CpGs were replicable in prior studies from Denmark or North America, resulting in 273 replicable CpG in girls and 67 CpGs in boys (236 and 68 genes, respectively). Most identified genes are known to be related to biological processes of puberty; however, genetic polymorphisms of only four of these genes were previously linked to pubertal markers in humans.LIMITATIONS, REASONS FOR CAUTIONThe relative age of pubertal onset to the age of DNAm measurements does not allow causal inference, since DNAm at an earlier age may have affected the pubertal age or pubertal age may have altered later DNAm. This investigation concentrates on autosomes. CpGs on X and Y chromosomes are not included in the current study.WIDER IMPLICATIONS OF THE FINDINGSAssessment of biological processes involved in pubertal transitions should include epigenetic information. Differential DNAm related to puberty needs to be investigated to determine whether it can act as an early marker for adult diseases known to be associated with puberty.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by NIH grants R03HD092776 (Epigenetic characterization of pubertal transitions) and R01AI121226. The 10-year follow-up of this study was funded by National Asthma Campaign, UK (Grant No 364), and the 18-year follow-up by a grant from the National Heart and Blood Institute (R01 HL082925). The authors have no conflicts to report.