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Asthma often remains uncontrolled, despite the fact that the pharmacological treatment has undergone large changes. We studied changes in the treatment of asthma over a 20-year period and identified factors associated with the regular use of inhaled corticosteroid (ICS) treatment. Changes in the use of medication were determined in 4617 randomly selected subjects, while changes in adults with persistent asthma were analysed in 369 participants. The study compares data from three surveys in 24 centres in 11 countries. The use of ICSs increased from 1.7% to 5.9% in the general population and the regular use of ICSs increased from 19% to 34% among persistent asthmatic subjects. The proportion of asthmatic subjects reporting asthma attacks in the last 12 months decreased, while the proportion that had seen a doctor in the last 12 months remained unchanged (42%). Subjects with asthma who had experienced attacks or had seen a doctor were more likely to use ICSs on a regular basis. Although ICS use has increased, only one-third of subjects with persistent asthma take ICSs on a regular basis. Less than half had seen a doctor during the last year. This indicates that underuse of ICSs and lack of regular healthcare contacts remains a problem in the management of asthma.

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p

BACKGROUND:Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS:We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS:First approach: 50 SNPs were selected based on an overall interaction effect at p

Background: Viral infections in childhood, especially to rhinovirus (RV) and respiratory syncytial virus (RSV), are associated with asthma inception and exacerbation. However, little is known about the role of RV- and RSV-specific antibodies in childhood versus adult asthma., Objective: We sought to investigate associations between RV- and RSV-specific IgG levels and asthma phenotypes in children and adults., Methods: The analysis included 1771 samples from participants of the Epidemiological Study on the Genetics and Environment of Asthma (530 children; age [mean ± SD], 11.1 ± 2.8, and 1241 adults; age [mean ± SD], 43.4 ± 16.7, among whom 274 and 498 had ever asthma, respectively). RSV- and RV-specific IgG levels were determined using microarrayed virus-derived antigens and peptides. Cross-sectional associations between standardized RSV- and RV-specific IgG levels and asthma phenotypes were estimated by multiple regression models., Results: In children, ever asthma was associated with higher IgG levels specific to RV, especially to RV-A and RV-C, and to RSV (adjusted odds ratios [95% CI] for a 1 - SD increase in IgG levels were 1.52 [1.16-1.99], 1.42 [1.10-1.83], and 1.24 [0.99-1.54], respectively). These associations were stronger for moderate to severe asthma than for mild asthma. Conversely in adults, ever asthma was associated with lower RV-A, RV-B, and RV-C IgG levels (adjusted odds ratios [95% CI] were 0.86 [0.74-0.99], 0.83 [0.73-0.95], and 0.85 [0.73-0.99], respectively)., Conclusions: Our results suggest that the association between respiratory virus-specific antibody levels and asthma varies during life, with asthma associated with higher levels of IgG to RSV, RV-A, and RV-C in children and lower levels of IgG responses to RV-A/B/C in adults., Competing Interests: This study was supported in part by NIRVANA (grant no. ANR-19-CE36-0005) and by the Danube Allergy Research Cluster Program (DARC-ARC 2.0) of the country of Lower Austria. Disclosure of potential conflict of interest: R. Valenta has received research grants from Worg Pharmaceuticals, HVD Biotech, and Viravaxx; and serves as a consultant for Viravaxx and Worg. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Asthma is a descriptive label for an obstructive inflammatory disease in the lower airways manifesting with symptoms including breathlessness, cough, difficulty in breathing, and wheezing. From a clinician's point of view, asthma symptoms can commence at any age, although most patients with asthma-regardless of their age of onset-seem to have had some form of airway problems during childhood. Asthma inception and related pathophysiologic processes are therefore very likely to occur early in life, further evidenced by recent lung physiologic and mechanistic research. Herein, we present state-of-the-art updates on the role of genetics and epigenetics, early viral and bacterial infections, immune response, and pathophysiology, as well as lifestyle and environmental exposures, in asthma across the life course. We conclude that early environmental insults in genetically vulnerable individuals inducing abnormal, pre-asthmatic airway responses are key events in asthma inception, and we highlight disease heterogeneity across ages and the potential shortsightedness of treating all patients with asthma using the same treatments. Although there are no interventions that, at present, can modify long-term outcomes, a precision-medicine approach should be implemented to optimize treatment and tailor follow-up for all patients with asthma.

Competing Interests: Conflict of interest: None declared.

Background: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation., Methods: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed., Results: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben., Conclusions: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Exposure to respiratory viruses is a significant cause of morbidity and affects virus-specific antibody levels. Little is known about determinants associated with immune response to these viruses. We aimed to investigate the determinants of respiratory syncytial virus (RSV)- and rhinovirus (RV)- specific IgG responses in both children and adults., Methods: The study is based on the EGEA cohort, composed of 530 samples of children in EGEA1 (1991-95) and 1241 samples of adults in EGEA2 (2003-07). Cumulative RV-specific IgG levels (species A, B and C) and IgG levels to RSV-G protein were measured by using micro-array technoloy. Multiple linear mixed models (random effect to account for familial dependence) were performed to assess associations between age, sex, body mass index (BMI), tobacco smoke exposure and season of blood sampling with RSV-and RV-specific IgG levels., Results: In children (11.1 ± 2.8 years old, 57% boys), higher RV-specific IgG levels were associated with older age (only for RV-B), female sex and lower BMI, while only older age was associated with higher RSV-specific IgG levels. In adults (43.5 ± 16.7 years old, 48% men), younger age, female sex, lower BMI, active smoking and all seasons except summer were associated with higher RV-specific IgG levels. Older age, active smoking and all seasons except summer were associated with higher RSV-specific IgG levels., Conclusion: Personal and seasonal determinants of RSV- and RV-specific IgG levels seem to vary according to the respiratory virus type and between children and adults, suggesting different patterns of responses along the life course., Competing Interests: Author RuV has received research grants from Worg Pharmaceuticals, Hangzhou, China, HVD Biotech, Vienna, Austria; and Viravaxx, Vienna, Austria. He serves as a consultant for Viravaxx and Worg. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Guillien, Niespodziana, Mauclin, Boudier, Varraso, Leynaert, Dumas, Le Moual, Schlederer, Bajic, Borochova, Errhalt, Vernet, Nadif, Bousquet, Bouzigon, Valenta and Siroux.)

Background: Intra-breath oscillometry has been proposed as a sensitive means of detecting airway obstruction in young children. We aimed to assess the impact of early life wheezing and lower respiratory tract illness on lung function, using both standard and intra-breath oscillometry in 3 year old children., Methods: History of doctor-diagnosed asthma, wheezing, bronchiolitis and bronchitis and hospitalisation for respiratory problems were assessed by questionnaires in 384 population-based children. Association of respiratory history with standard and intra-breath oscillometry parameters, including resistance at 7 Hz (R 7 ), frequency-dependence of resistance (R 7 - 19 ), reactance at 7 Hz (X 7 ), area of the reactance curve (AX), end-inspiratory and end-expiratory R (R eI , R eE ) and X (X eI , X eE ), and volume-dependence of resistance (ΔR = R eE -R eI ) was estimated by linear regression adjusted on confounders., Results: Among the 320 children who accepted the oscillometry test, 281 (88%) performed 3 technically acceptable and reproducible standard oscillometry measurements and 251 children also performed one intra-breath oscillometry measurement. Asthma was associated with higher R eI , R eE , ΔR and R 7 and wheezing was associated with higher ΔR. Bronchiolitis was associated with higher R 7 and AX and lower X eI and bronchitis with higher R eI . No statistically significant association was observed for hospitalisation., Conclusions: Our findings confirm the good success rate of oscillometry in 3-year-old children and indicate an association between a history of early-life wheezing and lower respiratory tract illness and lower lung function as assessed by both standard and intra-breath oscillometry. Our study supports the relevance of using intra-breath oscillometry parameters as sensitive outcome measures in preschool children in epidemiological cohorts., (© 2024. The Author(s).)

Oxidative stress is a prominent pathway for the health effects associated with fine particulate matter (PM 2.5 ) exposure. Oxidative potential (OP) of PM has been associated to several health endpoints, but studies on its impact on biomarkers of oxidative stress remains insufficient. 300 pregnant women from the SEPAGES cohort (France) carried personal PM 2.5 samplers for a week and OP was measured using ascorbic acid (AA) and dithiothreitol (DTT) assays, and normalized by 1) PM 2.5 mass (OP m ) and 2) sampled air volume (OP v ). A pool of three urine spots collected on the 7th day of PM sampling was analyzed for biomarkers, namely 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDA) and 8-isoprostaglandin-F2α (8-isoPGF2α). Associations were investigated using adjusted multiple linear regressions. OP effects were additionally investigated by stratifying by median PM 2.5 concentration (14 μg m -3 ). In the main models, no association was observed with 8-isoPGF2α, nor MDA. An interquartile range (IQR) increase in OP m AA exposure was associated with increased 8-OHdG (percent change: 6.2 %; 95 % CI: 0.2 % to 12.6 %). In the stratified analysis, exposure to OP m AA was associated with 8-OHdG for participants exposed to low levels of PM 2.5 (percent change: 11.4 %; 95 % CI: 3.3 % to 20.1 %), but not for those exposed to high levels (percent change: -1.0 %; 95 % CI: -10.6 % to 9.6 %). Associations for OP m DTT also followed a similar pattern (p-values for OP m AA -PM and OP m DTT -PM interaction terms were 0.12 and 0.11, respectively). Overall, our findings suggest that OP m AA may be associated with increased DNA oxidative damage. This association was not observed with PM 2.5 mass concentration exposure. The effects of OP m AA in 8-OHdG tended to be stronger at lower (below median) vs. higher concentrations of PM 2.5 . Further epidemiological, toxicological and aerosol research are needed to further investigate the OP m AA effects on 8-OHdG and the potential modifying effect of PM mass concentration on this association., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Previous studies identified some environmental and lifestyle factors independently associated with children respiratory health, but few focused on exposure mixture effects. This study aimed at identifying, in pregnancy and in childhood, combined urban and lifestyle environment profiles associated with respiratory health in children., Methods: This study is based on the European Human Early-Life Exposome (HELIX) project, combining six birth cohorts. Associations between profiles of pregnancy (38 exposures) and childhood (84 exposures) urban and lifestyle factors, identified by clustering analysis, and respiratory health were estimated by regression models adjusted for confounders., Results: Among the 1033 included children (mean ± standard-deviation (SD) age: 8.2 ± 1.6 years old, 47% girls) the mean ± SD forced expiratory volume in 1s (FEV 1 ) and forced vital capacity (FVC) were 99 ± 13% and 101 ± 14%, respectively, and 12%, 12% and 24% reported ever-asthma, wheezing and rhinitis, respectively. Four profiles of pregnancy exposures and four profiles of childhood exposures were identified. Compared to the reference childhood exposure profile (low exposures), two exposure profiles were associated with lower levels of FEV 1 . One profile was characterized by few natural spaces in the surroundings and high exposure to the built environment and road traffic. The second profile was characterized by high exposure to meteorological factors and low levels of all other exposures and was also associated with an increased risk of ever-asthma and wheezing. A pregnancy exposure profile characterized by high exposure levels to all risk factors, but a healthy maternal lifestyle, was associated with a lower risk of wheezing and rhinitis in children, compared to the reference pregnancy profile (low exposures)., Conclusion: This comprehensive approach revealed pregnancy and childhood profiles of urban and lifestyle exposures associated with lung function and/or respiratory conditions in children. Our findings highlight the need to pursue the study of combined exposures to improve prevention strategies for multifactorial diseases such as asthma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Outcome-wide analysis can offer several benefits, including increased power to detect weak signals and the ability to identify exposures with multiple effects on health, which may be good targets for preventive measures. Recently, advanced statistical multivariate techniques for outcome-wide analysis have been developed, but they have been rarely applied to exposome analysis. In this work, we provide an overview of a selection of methods that are well-suited for outcome-wide exposome analysis and are implemented in the R statistical software. Our work brings together six different methods presenting innovative solutions for typical problems arising from outcome-wide approaches in the context of the exposome, including dependencies among outcomes, high dimensionality, mixed-type outcomes, missing data records, and confounding effects. The identified methods can be grouped into four main categories: regularized multivariate regression techniques, multi-task learning approaches, dimensionality reduction approaches, and bayesian extensions of the multivariate regression framework. Here, we compare each technique presenting its main rationale, strengths, and limitations, and provide codes and guidelines for their application to exposome data. Additionally, we apply all selected methods to a real exposome dataset from the Human Early-Life Exposome (HELIX) project, demonstrating their suitability for exposome research. Although the choice of the best method will always depend on the challenges to be faced in each application, for an exposome-like analysis we find dimensionality reduction and bayesian methods such as reduced rank regression (RRR) or multivariate bayesian shrinkage priors (MBSP) particularly useful, given their ability to deal with critical issues such as collinearity, high-dimensionality, missing data or quantification of uncertainty., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The exposome concept aims to consider all environmental stressors simultaneously. The dimension of the data and the correlation that may exist between exposures lead to various statistical challenges. Some methodological studies have provided insight regarding the efficiency of specific modeling approaches in the context of exposome data assessed once for each subject. However, few studies have considered the situation in which environmental exposures are assessed repeatedly. Here, we conduct a simulation study to compare the performance of statistical approaches to assess exposome-health associations in the context of multiple exposure variables. Different scenarios were tested, assuming different types and numbers of exposure-outcome causal relationships. An application study using real data collected within the INMA mother-child cohort (Spain) is also presented. In the simulation experiment, assessed methods showed varying performance across scenarios, making it challenging to recommend a one-size-fits-all strategy. Generally, methods such as sparse partial least-squares and the deletion-substitution-addition algorithm tended to outperform the other tested methods (ExWAS, Elastic-Net, DLNM, or sNPLS). Notably, as the number of true predictors increased, the performance of all methods declined. The absence of a clearly superior approach underscores the additional challenges posed by repeated exposome data, such as the presence of more complex correlation structures and interdependencies between variables, and highlights that careful consideration is essential when selecting the appropriate statistical method. In this regard, we provide recommendations based on the expected scenario. Given the heightened risk of reporting false positive or negative associations when applying these techniques to repeated exposome data, we advise interpreting the results with caution, particularly in compromised contexts such as those with a limited sample size.

Background: Poly- and perfluoroalkyl substances (PFAS) are used in a wide range of products. Experimental studies suggested impaired lung development and pro-inflammatory response following exposure to some PFAS. We aimed to assess the associations between prenatal exposure to PFAS and children respiratory health., Methods: The study is based on 433 mother-child pairs. 26 PFAS were measured in maternal serum collected during pregnancy. Lung function parameters were measured at 2 months using tidal breathing flow-volume loops and multiple-breath nitrogen washout and at 36 months using oscillometry. Incidence of respiratory health diseases (asthma, wheeze, bronchitis, bronchiolitis) in the first 36 months of life was assessed by repeated questionnaires. A cluster-based analysis was applied to identify prenatal PFAS exposure patterns. Adjusted linear and logistic regressions were performed to assess the associations between PFAS exposure patterns as well as individual PFAS, and each respiratory health parameter., Results: We excluded 13 PFAS due to low quantification (<5%). Relying on the 13 remaining PFAS, we identified three exposure clusters, characterized by low (N = 163), medium (N = 236) and high (N = 51) pregnancy PFAS concentrations. Compared to children belonging to the low exposure group, children in the moderate exposure group had higher reactance at 7 Hz (X 7 ) and lower frequency dependence of resistance between 7 Hz and 19 Hz (R 7-19 ) at 36 months, suggesting better lung function. No association of any exposure metric was detected with respiratory diseases in the first 3 years of life., Conclusions: Our study relying on both mixture and uni-pollutant analyses, does not provide evidence for a deleterious effect of prenatal PFAS exposure on respiratory health at an early age., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: While the adverse effects of short-term ambient ozone exposure on lung function are well-documented, the impact of long-term exposure remains poorly understood, especially in adults., Methods: We aimed to investigate the association between long-term ozone exposure and lung function decline. The 3014 participants were drawn from 17 centers across eight countries, all of which were from the European Community Respiratory Health Survey (ECRHS). Spirometry was conducted to measure pre-bronchodilation forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) at approximately 35, 44, and 55 years of age. We assigned annual mean values of daily maximum running 8-h average ozone concentrations to individual residential addresses. Adjustments were made for PM 2.5 , NO 2 , and greenness. To capture the ozone-related change in spirometric parameters, our linear mixed effects regression models included an interaction term between long-term ozone exposure and age., Findings: Mean ambient ozone concentrations were approximately 65 μg/m³. A one interquartile range increase of 7 μg/m³ in ozone was associated with a faster decline in FEV 1 of -2.08 mL/year (95% confidence interval: -2.79, -1.36) and in FVC of -2.86 mL/year (-3.73, -1.99) mL/year over the study period. Associations were robust after adjusting for PM 2.5 , NO 2 , and greenness. The associations were more pronounced in residents of northern Europe and individuals who were older at baseline. No consistent associations were detected with the FEV 1 /FVC ratio., Interpretation: Long-term exposure to elevated ambient ozone concentrations was associated with a faster decline of spirometric lung function among middle-aged European adults over a 20-year period., Funding: German Research Foundation., Competing Interests: Marco Gnesi is currently an employee at AstraZeneca SpA; however, the research presented here has been conducted previously and AstraZeneca had no role in any phase of the research project. The authors have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Background: The few studies that have examined associations between greenspace and lung function in adulthood have yielded conflicting results and none have examined whether the rate of lung function decline is affected., Objective: We explored the association between residential greenspace and change in lung function over 20 years in 5559 adults from 22 centers in 11 countries participating in the population-based, international European Community Respiratory Health Survey., Methods: Forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) were measured by spirometry when participants were approximately 35 (1990-1994), 44 (1999-2003), and 55 (2010-2014) years old. Greenness was assessed as the mean Normalized Difference Vegetation Index (NDVI) in 500 m, 300 m, and 100 m circular buffers around the residential addresses at the time of lung function measurement. Green spaces were defined as the presence of agricultural, natural, or urban green spaces in a circular 300 m buffer. Associations of these greenspace parameters with the rate of lung function change were assessed using adjusted linear mixed effects regression models with random intercepts for subjects nested within centers. Sensitivity analyses considered air pollution exposures., Results: A 0.2-increase (average interquartile range) in NDVI in the 500 m buffer was consistently associated with a faster decline in FVC (-1.25 mL/year [95% confidence interval: -2.18 to -0.33]). These associations were especially pronounced in females and those living in areas with low PM 10 levels. We found no consistent associations with FEV 1 and the FEV 1 /FVC ratio. Residing near forests or urban green spaces was associated with a faster decline in FEV 1 , while agricultural land and forests were related to a greater decline in FVC., Conclusions: More residential greenspace was not associated with better lung function in middle-aged European adults. Instead, we observed slight but consistent declines in lung function parameters. The potentially detrimental association requires verification in future studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. SCD holds investigator initiated grants from Sanofi, GSK, and Astra Zenica for unrelated research. RJ reports grants from Estonian Research Council Personal Research Grant No. 562, during the conduct of the study; personal fees from Consultancy, grants from Grants/grants pending, personal fees from Payment for lectures, personal fees from Travel/accommodations/meeting expenses, outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exposure to phthalates and synthetic phenols is ubiquitous. Some of them are suspected to impact child respiratory health, although evidence still remains insufficient. This study investigated the associations between prenatal exposure to phthalates and phenols, individually and as a mixture, and child respiratory health assessed by objective lung function measures since 2 months of age. Among 479 mother-child pairs from the SEPAGES cohort, 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites were measured in 2 pools including each 21 urine samples collected at the 2nd and 3rd pregnancy trimesters. Lung function was measured at 2 months using tidal breathing flow-volume loops and nitrogen multiple-breath washout, and at 3 years using oscillometry. Asthma, wheezing, bronchitis and bronchiolitis were assessed by repeated questionnaires. A cluster-based analysis was applied to identify exposure patterns to phenols and phthalates. Adjusted associations between clusters as well as each individual exposure biomarker and child respiratory health were estimated by regression models. We identified four prenatal exposure patterns: 1) low concentrations of all biomarkers (reference, n = 106), 2) low phenols-moderate phthalates (n = 162), 3) high concentrations of all biomarkers except bisphenol S (n = 109), 4) high parabens-moderate other phenols-low phthalates (n = 102). At 2 months, cluster 2 infants had lower functional residual capacity and tidal volume and higher ratio of time to peak tidal expiratory flow to expiratory time (t PTEF /t E ) and cluster 3 had lower lung clearance index and higher t PTEF /t E . Clusters were not associated with respiratory health at 3 years but in the single-pollutant models, parabens were associated with increased area of the reactance curve, bronchitis (methyl, ethyl parabens) and bronchiolitis (propyl paraben). Our results suggested that prenatal exposure to mixtures of phthalates reduced lung volume in early life. Single exposure analyses suggested associations of parabens with impaired lung function and increased risk of respiratory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Early-life environmental exposures are suspected to be involved in the development of chronic diseases later in life. Most studies conducted so far considered single or few exposures and single-health parameter. Our study aimed to identify a childhood general health score and assess its association with a wide range of pre- and post-natal environmental exposures., Methods: The analysis is based on 870 children (6-12 years) from six European birth cohorts participating in the Human Early-Life Exposome project. A total of 53 prenatal and 105 childhood environmental factors were considered, including lifestyle, social, urban and chemical exposures. We built a general health score by averaging three sub-scores (cardiometabolic, respiratory/allergy and mental) built from 15 health parameters. By construct, a child with a low score has a low general health status. Penalized multivariable regression through Least Absolute Shrinkage and Selection Operator (LASSO) was fitted in order to identify exposures associated with the general health score., Findings: The results of LASSO show that a lower general health score was associated with maternal passive and active smoking during pregnancy and postnatal exposure to methylparaben, copper, indoor air pollutants, high intake of caffeinated drinks and few contacts with friends and family. Higher child's general health score was associated with prenatal exposure to a bluespace near residency and postnatal exposures to pets, cobalt, high intakes of vegetables and more physical activity. Against our hypotheses, postnatal exposure to organochlorine compounds and perfluorooctanoate were associated with a higher child's general health score., Conclusion: By using a general health score summarizing the child cardiometabolic, respiratory/allergy and mental health, this study reinforced previously suspected environmental factors associated with various child health parameters (e.g. tobacco, air pollutants) and identified new factors (e.g. pets, bluespace) warranting further investigations., (© 2023. The Author(s).)

Background: While biological age in adults is often understood as representing general health and resilience, the conceptual interpretation of accelerated biological age in children and its relationship to development remains unclear. We aimed to clarify the relationship of accelerated biological age, assessed through two established biological age indicators, telomere length and DNA methylation age, and two novel candidate biological age indicators, to child developmental outcomes, including growth and adiposity, cognition, behavior, lung function and the onset of puberty, among European school-age children participating in the HELIX exposome cohort., Methods: The study population included up to 1173 children, aged between 5 and 12 years, from study centres in the UK, France, Spain, Norway, Lithuania, and Greece. Telomere length was measured through qPCR, blood DNA methylation, and gene expression was measured using microarray, and proteins and metabolites were measured by a range of targeted assays. DNA methylation age was assessed using Horvath's skin and blood clock, while novel blood transcriptome and 'immunometabolic' (based on plasma proteins and urinary and serum metabolites) clocks were derived and tested in a subset of children assessed six months after the main follow-up visit. Associations between biological age indicators with child developmental measures as well as health risk factors were estimated using linear regression, adjusted for chronological age, sex, ethnicity, and study centre. The clock derived markers were expressed as Δ age (i.e. predicted minus chronological age)., Results: Transcriptome and immunometabolic clocks predicted chronological age well in the test set ( r =0.93 and r =0.84 respectively). Generally, weak correlations were observed, after adjustment for chronological age, between the biological age indicators.Among associations with health risk factors, higher birthweight was associated with greater immunometabolic Δ age, smoke exposure with greater DNA methylation Δ age, and high family affluence with longer telomere length.Among associations with child developmental measures, all biological age markers were associated with greater BMI and fat mass, and all markers except telomere length were associated with greater height, at least at nominal significance (p<0.05). Immunometabolic Δ age was associated with better working memory (p=4 e-3) and reduced inattentiveness (p=4 e-4), while DNA methylation Δ age was associated with greater inattentiveness (p=0.03) and poorer externalizing behaviors (p=0.01). Shorter telomere length was also associated with poorer externalizing behaviors (p=0.03)., Conclusions: In children, as in adults, biological aging appears to be a multi-faceted process and adiposity is an important correlate of accelerated biological aging. Patterns of associations suggested that accelerated immunometabolic age may be beneficial for some aspects of child development while accelerated DNA methylation age and telomere attrition may reflect early detrimental aspects of biological aging, apparent even in children., Funding: UK Research and Innovation (MR/S03532X/1); European Commission (grant agreement numbers: 308333; 874583)., Competing Interests: OR, CL, SJ, SA, EB, Pd, LC, HK, RG, KG, LM, DM, ES, VS, JU, MV, JW, TN, MB, MV No competing interests declared, (© 2023, Robinson et al.)