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Importance: Bone mass accrual is influenced by environmental and lifestyle factors. Targeted interventions at the early stages of life might decrease fracture and/or osteoporosis risk later in life., Objective: To investigate whether early-life exposure to residential surrounding green space is associated with a change in bone mineral density in young children., Design, Setting, and Participants: In this prospective birth cohort study (ENVIRONAGE [Environmental Influence on Aging in Early Life]), mother-child pairs from Flanders, Belgium, were recruited at birth and followed up for 4 to 6 years, between October 1, 2014, and July 31, 2021. Data analysis was conducted between January and February 2022., Exposures: Green space was estimated for high green (>3 m vegetation height), low green (≤3 m vegetation height ), and total green (sum of high and low) within several radii (100-3000 m) around the residence after geocoding of the addresses., Main Outcomes and Measures: Radial bone mineral density was assessed using quantitative ultrasound measurement at follow-up, measured as the mean of the axially transmitted speed of sound in meters per second. Multiple linear and logistic regression models were used while accounting for relevant covariates and potential confounders., Results: The study population comprised 327 children (180 [55.0%] female; mean [SD] age, 4.6 [0.4] years at the follow-up evaluation). Early-life exposure to residential green space was associated with increased childhood bone health. An IQR increment in total green (21.2%) and high green (19.9%) space within 500 m was associated with an increase of 27.38 m/s (95% CI, 9.63-45.13 m/s) and 25.30 m/s (95% CI, 7.93-42.68 m/s) in bone mineral density, respectively. Additionally, an IQR increase in total (25.2%) and high (23.2%) green space within 1000 m was associated with a 67% (odds ratio, 0.33; 95% CI, 0.17-0.61) and 61% (odds ratio, 0.39; 95% CI, 0.18-0.75) lower risk of having a bone density lower than the sex-specific 10th percentile (3567.6 m/s for girls and 3522.8 m/s for boys)., Conclusions and Relevance: In this study of children aged 4 to 6 years, higher bone mineral density and a lower risk of having low bone density were associated with higher residential green space exposure during childhood. These findings highlight the importance of early-life exposure to residential green space on bone health during critical periods of growth and development, with long-term implications.

Within collaborative projects, such as the EU-funded Horizon 2020 EXIMIOUS project (Mapping Exposure-Induced Immune Effects: Connecting the Exposome and the Immunome), collection and analysis of large volumes of data pose challenges in the domain of data management, with regards to both ethical and legal aspects. However, researchers often lack the right tools and/or accurate understanding of the ethical/legal framework to independently address such challenges. With the guidance and support within and between the partner institutes (the researchers and the ethical and legal teams) in the EXIMIOUS project, we have been able to understand and solve most challenges during the first two project years. This has fed into the development of a Data Management Plan and the establishment of data management platforms in accordance with the ethical and legal framework laid down by the EU and the different national regulations of the partners involved. Through this elaborate exercise, we have acquired tools which allow us to make our research data FAIR (Findable, Accessible, Interoperable, and Reusable), while at the same time ensuring data privacy and security (GDPR compliant). Herein we share our experience of creating and managing the data workflow through an open research communication, with the aim of helping other researchers build their data management framework in their own projects. Based on the measures adopted in EXIMIOUS to ensure FAIR data management, we also put together a checklist "DMP CHECK" containing a series of recommendations based on our experience., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Manosij Ghosh, Peter Hoet reports financial support was provided by H2020 874707., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cadmium (Cd) activates the DNA damage response (DDR) and inhibits the cell cycle in Arabidopsis thaliana through the transcription factor SUPPRESSOR OF GAMMA RESPONSE 1. The aim of this study was to investigate which individual leaf best reflects the Cd-induced effects on the regulation of the DDR and cell cycle progression in rosettes, enabling a more profound interpretation of the rosette data since detailed information, provided by the individual leaf responses, is lost when studying the whole rosette. Wild-type A. thaliana plants were cultivated in hydroponics and exposed to different Cd concentrations. Studied individual leaves were leaf 1 and 2, which emerged before Cd exposure, and leaf 3, which emerged upon Cd exposure. The DDR and cell cycle regulation were studied in rosettes as well as individual leaves after several days of Cd exposure. Varying concentration-dependent response patterns were observed between the entire rosette and individual leaves. Gene expression of selected DDR and cell cycle regulators showed higher similarity in their response between the rosette and the individual leaf emerged during Cd exposure than between both individual leaves. The same pattern was observed for plant growth and cell cycle-related parameters. We conclude that Cd-induced effects on the regulation of the DDR and cell cycle progression in the leaf that emerged during Cd exposure, resemble those observed in the rosette the most, which contributes to the interpretation of the rosette data in the framework of plant development and after exposure to Cd., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ann Cuypers has patent #Method for determining a toxicity and/or growth promotion effect of a treatment or compound (EP2022052518W) pending to Hasselt University., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear., Methods: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points., Results: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N)., Conclusions: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Knowledge of whether prenatal exposure to ambient air pollution disrupts steroidogenesis is currently lacking. We investigated the association between prenatal ambient air pollution and highly accurate measurements of cord blood steroid hormones from the androgenic pathway.This study included 397 newborns born between the years 2010 and 2015 from the ENVIRONAGE cohort in Belgium of whom six cord blood steroid levels were measured: 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, dehydroepiandrosterone, pregnenolone, androstenedione, and testosterone. Maternal ambient exposure to PM 2.5 (particles with aerodynamic diameter ≤ 2.5 μm), NO 2, and black carbon (BC) were estimated daily during the entire pregnancy using a high-resolution spatiotemporal model. The associations between the cord blood steroids and the air pollutants were tested and estimated by first fitting linear regression models and followed by fitting weekly prenatal exposures to distributed lag models (DLM). These analyses accounted for possible confounders, coexposures, and an interaction effect between sex and the exposure. We examined mixture effects and critical exposure windows of PM 2.5 , NO 2 and BC on cord blood steroids via the Bayesian kernel machine regression distributed lag model (BKMR-DLM).An interquartile range (IQR) increment of 7.96 µg/m 3 in PM 2.5 exposure during pregnancy trimester 3 was associated with an increase of 23.01% (99% confidence interval: 3.26-46.54%) in cord blood levels of 17α-hydroxypregnenolone, and an IQR increment of 0.58 µg/m³ in BC exposure during trimester 1 was associated with a decrease of 11.00% (99% CI: -19.86 to -0.012%) in cord blood levels of androstenedione. For these two models, the DLM statistics identified sensitive gestational time windows for cord blood steroids and ambient air pollution exposures, in particular for 17α-hydroxypregnenolone and PM 2.5 exposure during trimester 3 (weeks 28-36) and for androsterone and BC exposure during early pregnancy (weeks 2-13) as well as during mid-pregnancy (weeks 18-26). We identified interaction effects between pollutants, which has been suggested especially for NO 2 .Our results suggest that prenatal exposure to ambient air pollutants during pregnancy interferes with steroid levels in cord blood. Further studies should investigate potential early-life action mechanisms and possible later-in-life adverse effects of hormonal disturbances due to air pollution exposure., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Aim: Parabens are widely used as antimicrobial preservatives in personal care products. Studies investigating obesogenic or cardiovascular effects of parabens show discordant results, while data on preschool children are lacking. Paraben exposure during early childhood could have profound cardiometabolic effects later in life., Methods: In this cross-sectional study paraben concentrations [methyl (MeP), ethyl (EtP), propyl (PrP), butyl (BuP)] were measured by ultra-performance liquid chromatography/tandem mass spectrometry in 300 urinary samples of 4-6-year-old children of the ENVIRONAGE birth cohort. Paraben values below the limit of quantitation (LOQ) were imputed by censored likelihood multiple imputation. The associations between log-transformed paraben values and cardiometabolic measurements (BMI z-scores, waist circumference, blood pressure and retinal microvasculature) were analyzed in multiple linear regression models with a priori selected covariates. Effect modification by sex was investigated by including interaction terms., Results: Geometric means (geometric SD) of urinary MeP, EtP, and PrP levels above the LOQ were 32.60 (6.64), 1.26 (3.45), and 4.82 (4.11) μg/L, respectively. For BuP more than 96% of all measurements were below the LOQ. Regarding the microvasculature, we found direct associations between MeP and central retinal venular equivalent (β = 1.23, p = 0.039) and PrP with the retinal tortuosity index (x10 3) (β = 1.75, p = 0.0044). Furthermore, we identified inverse associations between MeP and ∑parabens with BMI z-scores (β = -0.067, p = 0.015 and β = -0.070, p = 0.014 respectively), and EtP with mean arterial pressure (β = -0.69, p = 0.048). The direction of association between EtP and BMI z-scores showed evidence for sex-specific differences with a direct trend in boys (β = 0.10, p = 0.060)., Conclusions: Already at young age paraben exposure is associated with potentially adverse changes in the retinal microvasculature., 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 Ltd. All rights reserved.)

Background: Ultrafine particles, including black carbon (BC), can reach the systemic circulation and therefore may distribute to distant organs upon inhalation. The kidneys may be particularly vulnerable to the adverse effects of BC exposure due to their filtration function., Objectives: We hypothesized that BC particles reach the kidneys via the systemic circulation, where the particles may reside in structural components of kidney tissue and impair kidney function., Methods: In kidney biopsies from 25 transplant patients, we visualized BC particles using white light generation under femtosecond-pulsed illumination. The presence of urinary kidney injury molecule-1 (KIM-1) and cystatin c (CysC) were evaluated with ELISA. We assessed the association between internal and external exposure matrices and urinary biomarkers using Pearson correlation and linear regression models., Results: BC particles could be identified in all biopsy samples with a geometric mean (5th, 95th percentile) of 1.80 × 10 3 (3.65 × 10 2 , 7.50 × 10 3 ) particles/mm 3 kidney tissue, predominantly observed in the interstitium (100 %) and tubules (80 %), followed by the blood vessels and capillaries (40 %), and the glomerulus (24 %). Independent from covariates and potential confounders, we found that each 10 % higher tissue BC load resulted in 8.24 % (p = 0.03) higher urinary KIM-1. In addition, residential proximity to a major road was inversely associated with urinary CysC (+10 % distance: -4.68 %; p = 0.01) and KIM-1 (+10 % distance: -3.99 %; p < 0.01). Other urinary biomarkers, e.g., the estimated glomerular filtration rate or creatinine clearance showed no significant associations., Discussion and Conclusion: Our findings that BC particles accumulate near different structural components of the kidney represent a potential mechanism explaining the detrimental effects of particle air pollution exposure on kidney function. Furthermore, urinary KIM-1 and CysC show potential as air pollution-induced kidney injury biomarkers for taking a first step in addressing the adverse effects BC might exert on kidney function., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H.B., M.A., and T.S.N. declare that aspects of the work are subject of a patent application (Method for detecting or quantifying carbon black and/or black carbon particles, US20190025215A1) filed by Hasselt University (Hasselt, Belgium) and KU Leuven (Leuven, Belgium). The remaining authors declare no competing interests. None of the funding agencies had a role in the design and conduct of the study, in the collection, analysis and interpretation of the data, or in the preparation, review, or approval of the manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Cognitive performances of schoolchildren have been adversely associated with both recent and chronic exposure to ambient air pollution at the residence. In addition, growing evidence indicates that exposure to green space is associated with a wide range of health benefits. Therefore, we aimed to investigate if surrounding green space at the residence improves cognitive performance of primary schoolchildren while taking into account air pollution exposure., Methods: Cognitive performance tests were administered repeatedly to a total of 307 primary schoolchildren aged 9-12y, living in Flanders, Belgium (2012-2014). These tests covered three cognitive domains: attention (Stroop and Continuous Performance Tests), short-term memory (Digit Span Forward and Backward Tests), and visual information processing speed (Digit-Symbol and Pattern Comparison Tests). Green space exposure was estimated within several radii around their current residence (50 m to 2000 m), using a aerial photo-derived high-resolution (1 m 2 ) land cover map. Furthermore, air pollution exposure to PM 2.5 and NO 2 during the year before examination was modelled for the child's residence using a spatial-temporal interpolation method., Results: An improvement of the children's attention was found with more residential green space exposure independent of traffic-related air pollution. For an interquartile range increment (21%) of green space within 100 m of the residence, a significantly lower mean reaction time was observed independent of NO 2 for both the sustained-selective (-9.74 ms, 95% CI: -16.6 to -2.9 ms, p = 0.006) and the selective attention outcomes (-65.90 ms, 95% CI: -117.0 to -14.8 ms, p = 0.01). Moreover, green space exposure within a large radius (2000 m) around the residence was significantly associated with a better performance in short-term memory (Digit-Span Forward Test) and a higher visual information processing speed (Pattern Comparison Test), taking into account traffic-related exposure. However, all associations were attenuated after taking into account long-term residential PM 2.5 exposure., Conclusions: Our panel study showed that exposure to residential surrounding green space was associated with better cognitive performances at 9-12 years of age, taking into account traffic-related air pollution exposure. These findings support the necessity to build attractive green spaces in the residential environment to promote healthy cognitive development in children., (© 2023. The Author(s).)

Background: Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming., Methods: Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings., Results: Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e-05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e-07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e-04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight., Conclusions: Our findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention., (© 2023. The Author(s).)

Mitochondria are sensitive to oxidative stress, which can be caused by traffic-related air pollution. Placental mitochondrial DNA (mtDNA) mutations have been previously linked with air pollution. However, the relationship between prenatal air pollution and cord-blood mtDNA mutations has been poorly understood. Therefore, we hypothesized that prenatal particulate matter (PM 2.5 ) and NO 2 exposures are associated with cord-blood mtDNA heteroplasmy. As part of the ENVIR ON AGE cohort, 200 mother-newborn pairs were recruited. Cord-blood mitochondrial single-nucleotide polymorphisms were identified by whole mitochondrial genome sequencing, and heteroplasmy levels were evaluated based on the variant allele frequency (VAF). Outdoor PM 2.5 and NO 2 concentrations were determined by a high-resolution spatial-temporal interpolation method based on the maternal residential address. Distributed lag linear models were used to determine sensitive time windows for the association between NO 2 exposure and cord-blood mtDNA heteroplasmy. A 5 μg/m 3 increment in NO 2 was linked with MT-D-Loop 16311T>C heteroplasmy from gestational weeks 17-25. MT-CYTB 14766C>T was negatively associated with NO 2 exposure in mid pregnancy, from weeks 14-17, and positively associated in late pregnancy, from weeks 31-36. No significant associations were observed with prenatal PM 2.5 exposure. This is the first study to show that prenatal NO 2 exposure is associated with cord-blood mitochondrial mutations and suggests two critical windows of exposure in mid-to-late pregnancy.

Background: Childhood cognitive development depends on neuroimmune interactions. Immunomodulation by early-life microbial exposure may influence neuropsychological function. In this study, we investigate the association between residential indoor microbiota and cognition and behavior among preschoolers., Results: Indoor-settled dust bacterial and fungal characteristics were assessed using 16S and ITS amplicon sequencing (microbial diversity) and qPCR measurements (microbial loads). Child behavior was assessed using four scales: peer relationship, emotional, conduct, and hyperactivity was assessed by the Strengths and Difficulties Questionnaire (SDQ). Cognitive function was assessed using four tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB) software. The first two tasks were designed to assess attention and psychomotor speed (Motor Screening (MOT) and Big/Little Circle (BLC)) and the last two to evaluate the child's visual recognition/working memory (Spatial Span (SSP) and Delayed Matching to Sample (DMS)). Among the 172 included children (age 4-6 years), we observed a 51% (95%CI;75%;9%) lower odds of children scoring not normal for hyperactivity and a decrease of 3.20% (95%CI, -6.01%; -0.30%) in BLC response time, for every IQR increase in fungal Shannon diversity. Contrarily, microbial loads were directly associated with SDQ scales and response time. For example, a 2-fold increase in Gram-positive bacterial load was associated with 70% (95%CI 18%; 156%) higher odds of scoring not normal for hyperactivity and an increase of 5.17% (95%CI 0.87%; 9.65%) in DMS response time., Conclusions: Our findings show that early-life exposure to diverse indoor fungal communities is associated with better behavioral and cognitive outcomes, whereas higher indoor microbial load was associated with worse outcomes. Video Abstract., (© 2022. The Author(s).)

Background: DNA methylation programming is sensitive to prenatal life environmental influences, but the impact of maternal exposure to green space on newborns DNA methylation has not been studied yet., Methods: We conducted a meta-epigenome-wide association study (EWAS) of maternal exposure to green space during gestation with cord blood DNA methylation in two subsets of the ENVIRONAGE cohort (N = 538). Cord blood DNA methylation was measured by Illumina HumanMethylation 450K in one subset (N = 189) and EPICarray in another (N = 349). High (vegetation height>3 m (m)), low (vegetation height<3 m) and total (including both) high-resolution green space exposures during pregnancy were estimated within 100 m and 1000 m distance around maternal residence. In each subset, we sought cytosine-phosphate-guanine (CpG) sites via linear mixed models adjusted on newborns' sex, ethnicity, gestational age, season at delivery, sampling day, maternal parity, age, smoking, education, and estimated blood cell proportions. EWASs results were meta-analysed via fixed-effects meta-analyses. Differentially methylated regions (DMRs) were identified via ENmix-combp and DMRcate algorithms. Sensitivity analyses were additionally adjusted on PM 2.5 , distance to major roads, urbanicity and neighborhood income. In the 450K subset, cord blood expression of differentially methylated genes was measured by Agilent microarrays and associated with green space., Results: 147 DMRs were identified, 85 of which were still significant upon adjustment for PM 2.5 , distance to major roads, urbanicity and neighborhood income, including HLA-DRB5, RPTOR, KCNQ1DN, A1BG-AS1, HTR2A, ZNF274, COL11A1 and PRSS36 DMRs. One CpG reached genome-wide significance, while 54 CpGs were suggestive significant (p-values<1e-05). Among them, a CpG, hypermethylated with 100 m buffer total green space, was annotated to PAQR9, whose expression decreased with 1000 m buffer low green space (p-value = 1.45e-05)., Conclusions: Our results demonstrate that maternal exposure to green space during pregnancy is associated with cord blood DNA methylation, mainly at loci organized in regions, in genes playing important roles in neurological development (e.g., HTR2A)., 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Particulate matter (PM) is associated with aging markers at birth, including telomeres and mitochondria. It is unclear whether markers of the core-axis of aging, i.e. tumor suppressor p53 (p53) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), are associated with prenatal air pollution and whether there are underlying mechanisms., Methods: 556 mother-newborn pairs from the ENVIRONAGE birth cohort were recruited at the East Limburg Hospital in Genk (Belgium). In placenta and cord blood, telomere length (TL) and mitochondrial DNA content (mtDNAc) were measured using quantitative real-time polymerase chain reaction (qPCR). In cord plasma, p53 and PGC-1α protein levels were measured using ELISA. Daily ambient PM 2.5 concentrations during gestation were calculated using a spatial temporal interpolation model. Distributed lag models (DLMs) were applied to assess the association between prenatal PM 2.5 exposure and each molecular marker. Mediation analysis was performed to test for underlying mechanisms., Results: A 5 µg/m 3 increment in PM 2.5 exposure was associated with -11.23 % (95 % CI: -17.36 % to -4.65 %, p = 0.0012) and -7.34 % (95 % CI: -11.56 % to -2.92 %, p = 0.0014) lower placental TL during the entire pregnancy and second trimester respectively, and with -12.96 % (95 % CI: -18.84 % to -6.64 %, p < 0.001) lower placental mtDNAc during the third trimester. Furthermore, PM 2.5  exposure was associated with a 12.42 % (95 % CI: -1.07 % to 27.74 %, p = 0.059) higher cord plasma p53 protein level and a -3.69 % (95 % CI: -6.97 % to -0.31 %, p = 0.033) lower cord plasma PGC-1α protein level during the third trimester. Placental TL mediated 65 % of the negative and 17 % of the positive association between PM 2.5 and placental mtDNAc and cord plasma p53 protein levels, respectively., Conclusion: Ambient PM 2.5 exposure during pregnancy is associated with markers of the core-axis of aging, with TL as a mediating factor. This study strengthens the hypothesis of the air pollution induced core-axis of aging, and may unravel a possible underlying mediating mechanism in an early-life epidemiological context., 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 © 2022. Published by Elsevier Ltd.)

Green space could influence adult cognition and childhood neurodevelopment , and is hypothesized to be partly driven by epigenetic modifications. However, it remains unknown whether some of these associations are already evident during foetal development. Similar biological signals shape the developmental processes in the foetal brain and placenta.Therefore, we hypothesize that green space can modify epigenetic processes of cognition-related pathways in placental tissue, such as DNA-methylation of the serotonin receptor HTR2A. HTR2A- methylation was determined within 327 placentas from the ENVIR ON AGE (ENVIRonmental influence ON early AGEing) birth cohort using bisulphite-PCR-pyrosequencing. Total green space exposure was calculated using high-resolution land cover data derived from the Green Map of Flanders in seven buffers (50 m-3 km) and stratified into low (<3 m) and high (≥3 m) vegetation. Residential nature was calculated using the Land use Map of Flanders. We performed multivariate regression models adjusted for several a priori chosen covariables. For an IQR increment in total green space within a 1,000 m, 2,000 m and 3,000 m buffer the methylation of HTR2A increased with 1.47% (95%CI:0.17;2.78), 1.52% (95%CI:0.21;2.83) and 1.42% (95%CI:0.15;2.69), respectively. Additionally,, we found 3.00% (95%CI:1.09;4.91) and 1.98% (95%CI:0.28;3.68) higher HTR2A- methylation when comparing residences with and without the presence of nature in a 50 m and 100 m buffer, respectively. The methylation status of HTR2A in placental tissue is positively associated with maternal green space exposure. Future research is needed to understand better how these epigenetic changes are related to functional modifications in the placenta and the consequent implications for foetal development.

Telomere length at birth determines later life telomere length and potentially predicts ageing-related diseases. However, the genetic and epigenetic settings of telomere length in newborns have not been analyzed. In addition, no study yet has reported how the interplay between genetic variants and genome-wide cytosine methylation explains the variation in early-life telomere length. In this study based on 281 mother-newborn pairs from the ENVIR ON AGE birth cohort, telomere length and whole-genome DNA methylation were assessed in cord blood and 26 candidate single nucleotide polymorphism related to ageing or telomere length were genotyped. We identified three genetic variants associated with cord blood telomere length and 57 cis methylation quantitative trait loci ( cis -mQTLs) of which 22 mQTLs confirmed previous findings and 35 were newly identified. Five SNPs were found to have significant indirect effects on cord blood telomere length via the mediating CpGs. The association between rs911874 ( SOD2 ) and newborn telomere length was modified by nearby DNA methylation indicated by a significant statistical interaction. Our results suggest that DNA methylation in cis might have a mediation or modification effect on the genetic difference in newborn telomere length. This novel approach warrants future follow-up studies that are needed to further confirm and extend these findings., Competing Interests: The 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., (Copyright © 2022 Wang, Alfano, Reimann, Hogervorst, Bustamante, De Vivo, Plusquin, Nawrot and Martens.)

Background: Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L 10550A>G heteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM 2.5 exposure is associated with cord blood MT-ND4L 10550A>G heteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L 10550A>G heteroplasmy in overweight during early childhood is investigated., Methods: This study included 386 mother-newborn pairs. Outdoor PM 2.5 concentrations were determined at the maternal residential address. Cord blood MT-ND4L 10550A>G heteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM 2.5 exposure on childhood overweight mediated by cord blood MT-ND4L 10550A>G heteroplasmy., Results: Prenatal PM 2.5 exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51; p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM 2.5 exposure was associated with cord blood MT-ND4L 10550A>G heteroplasmy from gestational week 9 - 13. The largest effect was observed in week 10, where a 5 µg/m 3 increment in PM 2.5 was linked with cord blood MT-ND4L 10550A>G heteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L 10550A>G heteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50; p = 0.02). The effect of prenatal PM 2.5 exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L 10550A>G heteroplasmy., Conclusions: Cord blood MT-ND4L 10550A>G heteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM 2.5 during the first trimester of pregnancy was associated with cord blood MT-ND4L 10550A>G heteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L 10550A>G heteroplasmy in the association between PM 2.5 exposure and childhood overweight., (© 2022. The Author(s).)

Background: Increasing evidence supports the concept of prenatal programming as an early factor in the aging process. DNA methylation age (DNAm age), global genome-wide DNA methylation (global methylation), telomere length (TL), and mitochondrial DNA content (mtDNA content) have independently been shown to be markers of aging, but their interrelationship and determinants at birth remain uncertain., Methods: We assessed the inter-correlation between the aging biomarkers DNAm age, global methylation, TL and mtDNA content using Pearson's correlation in 190 cord blood samples of the ENVIRONAGE birth cohort. TL and mtDNA content was measured via qPCR, while the DNA methylome was determined using the human 450K methylation Illumina microarray. Subsequently, DNAm age was calculated according to Horvath's epigenetic clock, and mean global, promoter, gene-body, and intergenic DNA methylation were determined. Path analysis, a form of structural equation modeling, was performed to disentangle the complex causal relationships among the aging biomarkers and their potential determinants., Results: DNAm age was inversely correlated with global methylation (r = -0.64, p < 0.001) and mtDNA content (r = - 0.16, p = 0.027). Cord blood TL was correlated with mtDNA content (r = 0.26, p < 0.001) but not with global methylation or DNAm age. Path analysis showed the strongest effect for global methylation on DNAm age with a decrease of 0.64 standard deviations (SD) in DNAm age for each SD (0.01%) increase in global methylation (p < 0.001). Among the applied covariates, newborn sex and season of delivery were the strongest determinants of aging biomarkers., Conclusions: We provide insight into molecular aging signatures at the start of life, including their interrelations and determinants, showing that cord blood DNAm age is inversely associated with global methylation and mtDNA content but not with newborn telomere length. Our findings demonstrate that cord blood TL and DNAm age relate to different pathways/mechanisms of biological aging and can be influenced by environmental factors already at the start of life. These findings are relevant for understanding fetal programming and for the early prevention of noncommunicable diseases., (© 2022. The Author(s).)

Background: Residential green space has been associated with mental health benefits, but how such associations vary with green space types is insufficiently known., Objective: We aimed to investigate associations between types and quantities of green space and sales of mood disorder medication in Belgium., Methods: We used aggregated sales data of psycholeptics and psychoanaleptics prescribed to adults from 2006 to 2014. Generalized mixed effects models were used to investigate associations between relative covers of woodland, low-green, grassland, and garden, and average annual medication sales. Models were adjusted for socio-economic background variables, urban-rural differences, and administrative region, and included random effects of latitude and longitude., Results: Urban census tracts were associated with 9-10% higher medication sales. In nationwide models, a 10% increase in relative cover of woodland, garden, and grass was associated with a 1-2% decrease in medication sales. The same association was found for low green but only for men. In stratified models, a 10% increase in relative cover of any green space type in urban census tracts was associated with a decrease of medication sales by 1-3%. In rural census tracts, no protective associations between green space and mood disorder medication sales were observed, with the exception of relative woodland cover for women (-1%), and low green was associated with higher medication sales (+6-7%)., Conclusions: Taken together, these results suggest that living in green environments may be beneficial for adult mental health. Woodland exposure seemed the most beneficial, but the amount of green space was more important than the type. Results underline the importance of conserving green space in our living environment, for the conservation of biodiversity and for human health., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Importance: Adult telomere length (TL) is a biological marker of aging associated with vascular health. TL at birth is associated with later life TL and may contain early biological information of later life cardiovascular health and disease., Objective: To evaluate whether newborn TL is associated with early life blood pressure differences in childhood., Design, Setting, and Participants: This cohort study was part of the ENVIRONAGE (Environmental Influence on Aging in Early Life) study, a birth cohort of Belgian mother-child pairs with recruitment at birth and a median follow-up of 4.5 years conducted between October 2014 and July 2021. Participants included for analysis provided full data for evaluation at follow-up visit. Data analysis was conducted between August and September 2021., Main Outcomes and Measures: Cord blood and placental average relative TL were measured at birth using quantitative polymerase chain reaction (qPCR). Systolic, diastolic, and mean arterial pressure (MAP) were evaluated at follow-up. High childhood blood pressure (standardized for child age, sex, and height) was defined following the 2017 American Academy of Pediatrics guidelines. Multivariable adjusted linear and logistic regression models were used to associate newborn TL and blood pressure indicators in childhood., Results: This study included 485 newborn children (52.8% girls) with a mean (SD) age of 4.6 (0.4) years at the follow-up visit. Newborn TL was associated with lower blood pressure in childhood. A 1-IQR increase in cord blood TL was associated with a -1.54 mm Hg (95% CI, -2.36 to -0.72 mm Hg) lower diastolic blood pressure and -1.18 mm Hg (95% CI, -1.89 to -0.46 mm Hg) lower MAP. No association was observed with systolic blood pressure. Furthermore, a 1-IQR increase in cord blood TL was associated with lower odds of having high blood pressure at the age of 4 to 6 years (adjusted OR, 0.72; 95% CI, 0.53 to 0.98). In placenta, a 1-IQR increase in TL was associated with a -0.96 mm Hg (95% CI, -1.72 to -0.21 mm Hg) lower diastolic, -0.88 mm Hg (95% CI, -1.54 to -0.22 mm Hg) lower MAP, and a lower adjusted OR of 0.69 (95% CI, 0.52 to 0.92) for having a high blood pressure in childhood., Conclusions and Relevance: In this prospective birth cohort study, variation in early life blood pressure at school-age was associated with TL at birth. Cardiovascular health may to some extent be programmed at birth, and these results suggest that TL entails a biological mechanism in this programming.

Background: The mechanisms underlying childhood overweight and obesity are poorly known. Here, we investigated the direct and indirect effects of different prenatal exposures on offspring rapid postnatal growth and overweight in childhood, mediated through cord blood metabolites. Additionally, rapid postnatal growth was considered a potential mediator on childhood overweight, alone and sequentially to each metabolite., Methods: Within four European birth-cohorts (N = 375 mother-child dyads), information on seven prenatal exposures (maternal education, pre-pregnancy BMI, weight gain and tobacco smoke during pregnancy, age at delivery, parity, and child gestational age), selected as obesogenic according to a-priori knowledge, was collected. Cord blood levels of 31 metabolites, associated with rapid postnatal growth and/or childhood overweight in a previous study, were measured via liquid-chromatography-quadrupole-time-of-flight-mass-spectrometry. Rapid growth at 12 months and childhood overweight (including obesity) between four and eight years were defined with reference to WHO growth charts. Single mediation analysis was performed using the imputation approach and multiple mediation analysis using the extended-imputation approach., Results: Single mediation suggested that the effect of maternal education, pregnancy weight gain, parity, and gestational age on rapid postnatal growth but not on childhood overweight was partly mediated by seven metabolites, including cholestenone, decenoylcarnitine(C10:1), phosphatidylcholine(C34:3), progesterone and three unidentified metabolites; and the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth. Multiple mediation suggested that the effect of gestational age on childhood overweight was mainly mediated by rapid postnatal growth and that the mediating role of the metabolites was marginal., Conclusion: Our findings provide evidence of the involvement of in utero metabolism in the propensity to rapid postnatal growth and of rapid postnatal growth in the propensity to childhood overweight. We did not find evidence supporting a mediating role of the studied metabolites alone between the studied prenatal exposures and the propensity to childhood overweight., (© 2022. The Author(s).)

A growing number of children born are conceived through in vitro fertilisation (IVF), which has been linked to an increased risk of adverse perinatal outcomes, as well as altered growth profiles and cardiometabolic differences in the resultant individuals. Some of these outcomes have also been shown to be influenced by the use of different IVF culture media and this effect is hypothesised to be mediated epigenetically, e.g. through the methylome. As such, we profiled the umbilical cord blood methylome of IVF neonates that underwent preimplantation embryo development in two different IVF culture media (G5 or HTF), using the Infinium Human Methylation EPIC BeadChip. We found no significant methylation differences between the two groups in terms of: (i) systematic differences at CpG sites or regions, (ii) imprinted sites/genes or birth weight-associated sites, (iii) stochastic differences presenting as DNA methylation outliers or differentially variable sites, and (iv) epigenetic gestational age acceleration., (© 2022. The Author(s).)

Green spaces are associated with increased well-being and reduced risk of developing psychiatric disorders. In this study, we aimed to investigate how residential proximity to green spaces was associated with stress response buffering during the COVID-19 pandemic in a prospective cohort of young mothers. We collected information on stress in 766 mothers (mean age: 36.6 years) from the ENVIRONAGE birth cohort at baseline of the study (from 2010 onwards), and during the COVID-19 pandemic (from December 2020 until May 2021). Self-reported stress responses due to the COVID-19 pandemic were the outcome measure. Green space was quantified in several radiuses around the residence based on high-resolution (1 m 2 ) data. Using ordinal logistic regression, we estimated the odds of better resistance to reported stress, while controlling for age, socio-economic status, stress related to care for children, urbanicity, and household change in income during the pandemic. In sensitivity analyses we corrected for pre-pandemic stress levels, BMI, physical activity, and changes in health-related habits during the pandemic. We found that for an inter-quartile range contrast in residential green space 300 m and 500 m around the residence, participants were respectively 24% (OR = 1.24, 95%CI: 1.03 to 1.51) and 29% (OR = 1.29, 95%CI: 1.04 to 1.60) more likely to be in a more resistant category, independent of the aforementioned factors. These results remained robust after additionally controlling for pre-pandemic stress levels, BMI, physical activity, smoking status, urbanicity, psychological disorders, and changes in health-related habits during the pandemic. This prospective study in young mothers highlights the importance of proximity to green spaces, especially during challenging times., (Copyright © 2021. Published by Elsevier Inc.)

Background: The available evidence for positive associations between urban trees and human health is mixed, partly because the assessment of exposure to trees is often imprecise because of, for instance, exclusion of trees in private areas and the lack of three-dimensional (3D) exposure indicators (e.g., crown volume)., Objectives: We aimed to quantify all trees and relevant 3D structural traits in Brussels (Belgium) and to investigate associations between the number of trees, tree traits, and sales of medication commonly prescribed for mood disorders and cardiovascular disease., Methods: We developed a workflow to automatically isolate all individual trees from airborne light detection and ranging (LiDAR) data collected in 2012. Trait data were subsequently extracted for 309,757 trees in 604 census tracts. We used the average annual age-standardized rate of medication sales in Brussels for the period 2006 to 2014, calculated from reimbursement information on medication prescribed to adults (19-64 years of age). The medication sales data were provided by sex at the census tract level. Generalized log-linear models were used to investigate associations between the number of trees, the crown volume, tree structural variation, and medication sales. Models were run separately for mood disorder and cardiovascular medication and for men and women. All models were adjusted for indicators of area-level socioeconomic status., Results: Single-factor models showed that higher stem densities and higher crown volumes are both associated with lower medication sales, but opposing associations emerged in multifactor models. Higher crown volume [an increase by one interquartile range  ( IQR )  of  1.4 × 10 4   m ³ / ha ] was associated with 34% lower mood disorder medication sales [women, β = - 0.341 (95% CI: - 0.379 , - 0.303 ); men, β = - 0.340 (95% CI: - 0.378 , - 0.303 )] and with 21-25% lower cardiovascular medication sales [women, β = - 0.214 (95% CI: - 0.246 , - 0.182 ); men, β = - 0.252 (95% CI: - 0.285 , - 0.219 )]. Conversely, a higher stem density (an increase by one IQR of  21.8  trees / ha ) was associated with 28-32% higher mood disorder medication sales [women, β = 0.322 (95% CI: 0.284, 0.361); men, β = 0.281 (95% CI: 0.243, 0.319)] and with 20-24% higher cardiovascular medication sales [women, β = 0.202 (95% CI: 0.169, 0.236); men, β = 0.240 (95% CI: 0.206, 0.273)]., Discussion: We found a trade-off between the number of trees and the crown volumes of those trees for human health benefits in an urban environment. Our results demonstrate that conserving large trees in urban environments may not only support conservation of biodiversity but also human health. https://doi.org/10.1289/EHP9924.

Introduction: During early childhood, neuronal networks are highly susceptible to environmental factors. Previous research suggests that green space exposure is beneficial for cognitive functioning. Here, we investigate the associations between residential green space exposure and behavioral problems and cognitive development in children aged four to six years., Method: We included children participating in the ENVIRONAGE birth cohort. Residential green spaces were calculated based on high-resolution land cover data within several buffers (50-1,000 m) around the residence. The children's behavior was assessed with the Strengths and Difficulties Questionnaire (SDQ) among 411 children. In addition, to evaluate cognitive function, 456 children completed four tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We used multivariate logistic and linear regression models while accounting for potential confounders and covariables., Results: An interquartile (IQR) increase of residential green space within 50 m was associated with a 38% (95% CI: 56;14) lower odds of a child having hyperactivity problems. Additionally, we found a beneficial influence of residential green space in close proximity (50-100 m) on the attention and psychomotor speed, represented by the Motor Screening Task. For example, we found a decrease of 0.45 (95% CI: -0.82;-0.09) pixel units from target center with an IQR increase of residential green space in a 50 m buffer. In addition, we observed an improved visual recognition/working memory, represented by the Delayed Matching to Sample Task within all included buffers (50-1000 m). For example, we observed a decrease of 4.91% (95 %CI: -7.46;-2.36) probability of an error occurring if the previous trial was correct and a 2.02% (95 %CI: 0.08; 3.97) increase of correct trials with an IQR increase of green space within a 100 m buffer., Conclusion: This study provides additional indications for a beneficial influence of green space exposure on the development of behavioral problems and cognitive function as young as four years of age., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations., Research Design and Methods: To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression., Results: Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] -0.013 [2.1 × 10-3], P value corrected for false discovery rate [PFDR] = 5.1 × 10-3) and cg02988288 (β [SE]-0.013 [2.3 × 10-3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm., Conclusions: Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses., (© 2022 by the American Diabetes Association.)

Background: Although a growing body of research has shown that exposure to nature has restorative effects on human health, the potential beneficial effects of nature-based interventions in the working environment are still underexplored., Methods: We performed a randomized controlled study with a nature-based program during working hours. We enrolled employees, randomized the participants into two groups being an intervention and a control group. Twice a week for three consecutive weeks, the intervention group participated in nature-based activities for 2 h. The primary outcomes were cognitive performance, burnout assessment, salivary cortisol levels, and continuous stress levels. We performed intervention-response analyses using mixed-effects models that included random effects for each participant across the different examinations., Results: Compared to the control group (n = 20), the intervention group (n = 25) participating in the nature-based program had a lower Burnout Assessment Tool score (-14.9% CI-16.2 to -14.3, difference; p < 0.001), lower salivary cortisol levels (-29.3% CI-34.7 to -25.3; p < 0.001) and higher visual information processing speed (7.4% CI6.9-8.0; p < 0.001). Selective attention of the participants that participated in the nature-based program improved during the interventions (-10.6 CI-19.6 to -6.9, p = 0.045), compared to the controls., Conclusions: This study provides novel evidence that exposure to nature during work hours reduces stress and improves cognitive performance. The trial is registered with ClinicalTrials.gov, number: NCT04111796., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background/aim: Glyphosate, a broad-spectrum herbicide, and its main metabolite aminomethylphosphonic acid (AMPA) are persistent in the environment. Studies showed associations between glyphosate or AMPA exposure and several adverse cellular processes, including metabolic alterations and oxidative stress., Objective: To determine the association between glyphosate and AMPA exposure and biomarkers of biological aging., Methods: We examined glyphosate and AMPA exposure, mtDNA content and leukocyte telomere length in 181 adults, included in the third cycle of the Flemish Environment and Health Study (FLEHSIII). DNA was isolated from leukocytes and the relative mtDNA content and telomere length were determined using qPCR. Urinary glyphosate and AMPA concentrations were measured by Gas Chromatography-Tandem Mass Spectrometry (GC-MS-MS). We used multiple linear regression models to associate mtDNA content and leukocyte telomere length with glyphosate or AMPA exposure while adjusting for confounding variables., Results: A doubling in urinary AMPA concentration was associated with 5.19% (95% CI: 0.49 to 10.11; p = 0.03) longer leukocyte telomere length, while no association was observed with urinary glyphosate concentration. No association between mtDNA content and urinary glyphosate nor AMPA levels was observed., Conclusions: This study showed that AMPA exposure may be associated with telomere biology in adults., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Aging starts at the beginning of life as evidenced by high variability in telomere length (TL) and mitochondrial DNA content (mtDNAc) at birth. Whether p53 and PGC-1α are connected to these age-related markers in early life is unclear. In this study, we hypothesized that these hallmarks of aging are associated at birth. In 613 newborns from the ENVIRONAGE birth cohort, p53 and PGC-1α protein levels were measured in cord plasma, while TL and mtDNAc were measured in both cord blood and placental tissue. Cord blood methylation data of genes corresponding to the measured protein levels were available from the Human MethylationEPIC 850K BeadChip array. Pearson correlations and linear regression models were applied while accounting for selected covariates. In cord, a 10% increase in TL was associated with 5.22% (95% CI: 3.26 to 7.22; p < 0.0001) higher mtDNAc and -2.66% (95% CI: -5.04 to -0.23%; p = 0.032) lower p53 plasma level. In placenta, a 10% increase in TL was associated with 5.46% (95% CI: 3.82 to 7.13%; p < 0.0001) higher mtDNAc and -2.42% (95% CI: -4.29 to -0.52; p = 0.0098) lower p53 plasma level. Methylation level of TP53 was correlated with TL and mtDNAc in cord blood and with cord plasma p53 level. Our study suggests that p53 may be an important factor both at the protein and methylation level for the telomere-mitochondrial axis of aging at birth.

Background: Ambient fine particulate matter (PM < 2.5 μm, PM 2.5 ) is gaining increasing attention as an environmental risk factor for health. The kidneys are considered a particularly vulnerable target to the toxic effects that PM 2.5 exerts. Alteration of kidney function may lead to a disrupted homeostasis, affecting disparate tissues in the body. This review intends to summarize all relevant knowledge published between January 2000 and December 2021 on the effects of ambient PM 2.5 and the adverse effects on kidney function in adults (≥ 18 years)., Results and Discussion: Studies published in peer-reviewed journals, written in English, regarding the effects of PM 2.5 on kidney function and the development and/or exacerbation of kidney disease(s) were included. Of the 587 nonduplicate studies evaluated, 40 were included, comprising of studies on healthy or diagnosed with pre-existing disease (sub)populations. Most of the studies were cohort studies (n = 27), followed by 10 cross-sectional, 1 ecological and 2 time-series studies. One longitudinal study was considered intermediate risk of bias, the other included studies were considered low risk of bias. A large portion of the studies (n = 36) showed that PM 2.5 exposure worsened kidney outcome(s) investigated; however, some studies show contradictory results. Measurement of the estimated glomerular filtration rate, for instance, was found to be positively associated (n = 8) as well as negatively associated (n = 4) with PM 2.5 ., Limitations and Conclusion: The main limitations of the included studies include residual confounding (e.g., smoking) and lack of individual exposure levels. The majority of included studies focused on specific subpopulations, which may limit generalizability. Evidence of the detrimental effects that ambient PM 2.5 may exert on kidney function is emerging. However, further investigations are required to determine how and to what extent air pollution, specifically PM 2.5 , exerts adverse effects on the kidney and alters its function., Registration: The systematic review protocol was submitted and published by the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020175615 )., (© 2022. The Author(s).)

Immune-mediated, noncommunicable diseases-such as autoimmune and inflammatory diseases-are chronic disorders, in which the interaction between environmental exposures and the immune system plays an important role. The prevalence and societal costs of these diseases are rising in the European Union. The EXIMIOUS consortium-gathering experts in immunology, toxicology, occupational health, clinical medicine, exposure science, epidemiology, bioinformatics, and sensor development-will study eleven European study populations, covering the entire lifespan, including prenatal life. Innovative ways of characterizing and quantifying the exposome will be combined with high-dimensional immunophenotyping and -profiling platforms to map the immune effects (immunome) induced by the exposome. We will use two main approaches that "meet in the middle"-one starting from the exposome, the other starting from health effects. Novel bioinformatics tools, based on systems immunology and machine learning, will be used to integrate and analyze these large datasets to identify immune fingerprints that reflect a person's lifetime exposome or that are early predictors of disease. This will allow researchers, policymakers, and clinicians to grasp the impact of the exposome on the immune system at the level of individuals and populations., Competing Interests: S.V. is the legal representative of STEVOH BV. STEVOH BV has been appointed as Managing director of the non-profit organisation BeCOH. S.V. works for the Nickel Institute, a global association of primary nickel producers. S.V. also works as external industrial hygiene consultant for many companies and associations in the context of the NEPSI, European Network for Silica. The views expressed are entirely those of the authors and do not necessarily reflect the Nickel Institute or NEPSI policy. All remaining authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Competing Interests: The 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 handling editor declared a past collaboration with one of the authors OR.

Introduction: Previous studies suggested that green space is beneficial for the cognitive development in children. However, evidence in adolescents is limited. Therefore, we aim to investigate green space exposure in association with attention and behaviour in adolescents., Methods: This study includes 596 Flemish adolescents between 13 and 17 years old. Attention was assessed with Stroop Test (selective attention) and Continuous Performance Test (sustained and selective attention). Behaviour was determined based on the Strengths and Difficulties Questionnaire. Green space was estimated in several radius distances around their current residence and school based on high-resolution land cover data. Multilevel regression analyses were used adjusting for participant's age, sex, education level of the mother, and area deprivation index., Results: Surrounding green space in a 2000 m radius is associated with a faster reaction time in adolescents. An IQR (13%) increment in total green space within 2000 m of the residence and school combined, is associated with a 32.7 ms (95% CI: -58.9 to -6.5; p = 0.02) and a 7.28 ms (95% CI: -11.7 to -2.8; p = 0.001) shorter mean reaction time between the presentation of a stimulus and the response based on the Stroop Test and the Continuous Performance Test. Subdividing green space based on vegetation height, shows that green space higher than 3 m is associated with a faster reaction time of the Continuous Performance Test (-6.50 ms; 95% CI: -10.9 to -2.2; p = 0.004), while low green is not. We did not find an association between green space and behavioural development in adolescents., Conclusions: Our study shows that green space, especially trees, surrounding the residence and school combined is associated with better sustained and selected attention in adolescents. These findings indicate that the availability of green is important for adolescents that are growing up in a rapidly urbanizing world., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Childhood obesity has become a global epidemic and carries significant long-term consequences to physical and mental health. Metabolomics, the global profiling of small molecules or metabolites, may reveal the mechanisms of development of childhood obesity and clarify links between obesity and metabolic disease. A systematic review of metabolomic studies of childhood obesity was conducted, following Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, searching across Scopus, Ovid, Web of Science and PubMed databases for articles published from January 1, 2005 to July 8, 2020, retrieving 1271 different records and retaining 41 articles for qualitative synthesis. Study quality was assessed using a modified Newcastle-Ottawa Scale. Thirty-three studies were conducted on blood, six on urine, three on umbilical cord blood, and one on saliva. Thirty studies were primarily cross-sectional, five studies were primarily longitudinal, and seven studies examined effects of weight-loss following a life-style intervention. A consistent metabolic profile of childhood obesity was observed including amino acids (particularly branched chain and aromatic), carnitines, lipids, and steroids. Although the use of metabolomics in childhood obesity research is still developing, the identified metabolites have provided additional insight into the pathogenesis of many obesity-related diseases. Further longitudinal research is needed into the role of metabolic profiles and child obesity risk., (© 2021 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

The tremendous increase in childhood obesity prevalence over the last few decades cannot merely be explained by genetics and evolutionary changes in the genome, implying that gene-environment interactions, such as epigenetic modifications, likely play a major role. This systematic review aims to summarize the evidence of the association between epigenetics and childhood obesity. A literature search was performed via PubMed and Scopus engines using a combination of terms related to epigenetics and pediatric obesity. Articles studying the association between epigenetic mechanisms (including DNA methylation and hydroxymethylation, non-coding RNAs, and chromatin and histones modification) and obesity and/or overweight (or any related anthropometric parameters) in children (0-18 years) were included. The risk of bias was assessed with a modified Newcastle-Ottawa scale for non-randomized studies. One hundred twenty-one studies explored epigenetic changes related to childhood obesity. DNA methylation was the most widely investigated mechanism (N = 101 studies), followed by non-coding RNAs (N = 19 studies) with evidence suggestive of an association with childhood obesity for DNA methylation of specific genes and microRNAs (miRNAs). One study, focusing on histones modification, was identified. Heterogeneity of findings may have hindered more insights into the epigenetic changes related to childhood obesity. Gaps and challenges that future research should face are herein described., (© 2021 World Obesity Federation.)

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits., Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268)., Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10 -7 ) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10 -6 ) in older children and had methylation differences in the same direction., Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: A growing body of evidence indicates that cardiovascular health in adulthood, particularly that of the microcirculation, could find its roots during prenatal development. In this study, we investigated the association between pre- and postnatal air pollution exposure on heat-induced skin hyperemia as a dynamic marker of the microvasculature., Methods: In 139 children between the ages of 4 and 6 who are followed longitudinally within the ENVIRONAGE birth cohort, we measured skin perfusion by Laser Doppler probes using the Periflux6000. Residential black carbon (BC), particulate (PM 10 and PM 2.5 ) air pollution, and nitrogen dioxide (NO 2 ) levels were modelled for each participant's home address using a high-resolution spatiotemporal model for multiple time windows. We assessed the association between skin hyperemia and pre- and postnatal air pollution using multiple regression models while adjusting for relevant covariates., Results: Residential BC exposure during the whole pregnancy averaged (IQR) 1.42 (1.22-1.58) µg/m 3 , PM 10 18.88 (16.64 - 21.13) µg/m 3 , PM 2.5 13.67 (11.5 - 15.56) µg/m 3 and NO 2 18.39 (15.52 - 20.31) µg/m 3 . An IQR increment in BC exposure during the third trimester of pregnancy was associated with an 11.5 % (95% CI: -20.1 to -1.9; p = 0.020) lower skin hyperemia. Similar effect estimates were retrieved for PM 10 , PM 2.5 and NO 2 (respectively 13.9 % [95% CI: -21.9 to -3.0; p = 0.003], 17.0 % [95% CI: -26.7 to -6.1; p = 0.004] and 12.7% [95 % CI: -22.2 to -1.9; p = 0.023] lower skin hyperemia). In multipollutant models, PM 2.5 showed the strongest inverse association with skin hyperemia. Postnatal exposure to BC, PM 10 , PM 2.5 or NO 2 , was not associated with skin hyperemia at the age of 4 to 6, and did not alter the previous reported prenatal associations when taken into account., Conclusion: Our findings support that BC, particulate air pollution, and NO 2 exposure, even at low concentrations, during prenatal life, can have long-lasting consequences for the microvasculature. This proposes a role of prenatal air pollution exposures over and beyond postnatal exposure in the microvascular alterations which were persistent into childhood., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Parabens are used as antimicrobial preservatives in personal care products. Few studies have dealt with adverse health outcomes, transplacental transfer, and obesogenic effects of prenatal exposure to parabens. We examined the association between placental paraben levels and cord blood metabolic biomarkers, considering modulating effects of maternal pre-pregnancy BMI and underlying epigenetic mechanisms, and investigated longitudinal effects of in utero paraben exposure on early childhood trajectories of BMI z-scores., Methods: Placental concentrations of four parabens [methyl (MeP), ethyl (EtP), propyl (PrP), and butyl (BuP)] were measured by ultra-performance liquid chromatography/tandem mass spectrometry in 229 placentas of the ENVIRONAGE birth cohort. The association with cord blood metabolic biomarkers [glucose, insulin, γ-glutamyltransferase (GGT), high-density and low-density lipoprotein (HDL and LDL)] was analyzed in multiple regression models with two different sets of, a priori selected potential confounders, additionally stratified for different maternal BMI groups and assessed by causal mediation analysis. The association between placental paraben concentration and differential DNA methylation of CpGs annotated to GGT and longitudinal measurements of BMI z-scores were investigated with adjusted linear mixed models., Results: The geometric means of placental MeP, EtP, PrP, and BuP levels above the limit of detection (LOD) were 4.42, 1.32, 1.51, and 0.35 ng/g respectively, with only EtP showing sufficient (88%) measurements above LOD for further analyses. An interquartile ratio (IQR) increase in placental EtP was associated with an increase of 12.61 % (95% CI: 1.80 24.57) in the geometric mean of cord GGT activity, and with a decrease of -3.64 % (95% CI: -6.80 to -0.39) in the geometric mean of cord glucose. Placental EtP levels were significantly associated with hypermethylation of cg08612779 annotated to GGT7 after correcting for multiple testing (ß = 0.0017, p = 0.049). An interquartile ratio (IQR) increment in placental EtP was associated with a decrease in longitudinal BMI z-score of 0.27 points (95% CI: -0.46 to -0.088)., Conclusion: Prenatal EtP exposure may affect early childhood BMI. The association of placental EtP with cord blood GGT and glucose levels provides a starting point for further research on mechanisms of paraben-related metabolic processes in utero., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Metabolomics may identify biological pathways predisposing children to the risk of overweight and obesity. In this study, we have investigated the cord blood metabolic signatures of rapid growth in infancy and overweight in early childhood in four European birth cohorts., Methods: Untargeted liquid chromatography-mass spectrometry metabolomic profiles were measured in cord blood from 399 newborns from four European cohorts (ENVIRONAGE, Rhea, INMA and Piccolipiu). Rapid growth in the first year of life and overweight in childhood was defined with reference to WHO growth charts. Metabolome-wide association scans for rapid growth and overweight on over 4500 metabolic features were performed using multiple adjusted logistic mixed-effect models and controlling the false discovery rate (FDR) at 5%. In addition, we performed a look-up analysis of 43 pre-annotated metabolites, previously associated with birthweight or rapid growth., Results: In the Metabolome-Wide Association Study analysis, we identified three and eight metabolites associated with rapid growth and overweight, respectively, after FDR correction. Higher levels of cholestenone, a cholesterol derivative produced by microbial catabolism, were predictive of rapid growth (p = 1.6 × 10 -3 ). Lower levels of the branched-chain amino acid (BCAA) valine (p = 8.6 × 10 -6 ) were predictive of overweight in childhood. The area under the receiver operator curve for multivariate prediction models including these metabolites and traditional risk factors was 0.77 for rapid growth and 0.82 for overweight, compared with 0.69 and 0.69, respectively, for models using traditional risk factors alone. Among the 43 pre-annotated metabolites, seven and five metabolites were nominally associated (P < 0.05) with rapid growth and overweight, respectively. The BCAA leucine, remained associated (1.6 × 10 -3 ) with overweight after FDR correction., Conclusion: The metabolites identified here may assist in the identification of children at risk of developing obesity and improve understanding of mechanisms involved in postnatal growth. Cholestenone and BCAAs are suggestive of a role of the gut microbiome and nutrient signalling respectively in child growth trajectories., (© 2021. The Author(s).)

Telomere length (TL) and telomere shortening are biological indicators of aging, and epigenetic associates have been found for TL in adults. However, the role of epigenetic signatures in setting newborn TL and early life telomere dynamics is unknown. In the present study, based on 247 participating newborns from the ENVIR ON AGE birth cohort, whole-genome DNA methylation, profiled on the Illumina MethylationEPIC BeadChip microarray, and TL were measured in cord blood. In a follow-up visit at a mean age of 4.58 years, leukocyte TL was evaluated. We combined an epigenome-wide association study and a statistical learning method with re-sampling to select CpGs and their two-way interactions to model baseline (cord blood) TL and early-life telomere attrition rate, where distinct epigenetic signatures were identified for the two outcomes. In addition, a stronger epigenetic regulation was suggested in setting newborn TL than that of telomere dynamics in early life: 47 CpGs and 7 between-CpG interactions explained 76% of the variance in baseline TLs, while 72% of the total variance in telomere attrition rate was explained by 31 CpGs and 5 interactions. Functional enrichment analysis based on the selected CpGs in the two models revealed GLUT4 translocation and immune cell signaling pathways, respectively. These CpGs and interactions, as well as the cellular pathways, are potential novel targets of further investigation of telomere biology and aging.

Background: The micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and β-cell activity., Methods: We assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIRONAGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and β-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and β-cell activity for a 5 μg/kg increase in placental iodine., Results: Higher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load (β = - 4.8%; 95%CI - 8.9 to - 0.6%; p = 0.026)., Conclusions: Higher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and β-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.

Background: Pro-inflammatory conditions such as air pollution might induce biological ageing. However, the available evidence on such an impact in children is still very scarce. We studied in primary schoolchildren the association of ambient residential air pollution exposure with telomere length (TL) and mitochondrial DNA content (mtDNAc), two important targets of the core axis of ageing., Methods: Between 2012 and 2014, buccal TL and mtDNAc were repeatedly assessed using qPCR in 197 Belgian primary schoolchildren (mean age 10.3 years) as part of the COGNAC study. At the child's residence, recent (week), sub-chronic (month) and chronic (year) exposure to nitrogen dioxide (NO 2 ), particulate matter ≤ 2.5 µm (PM 2.5 ) and black carbon (BC) were estimated using a high resolution spatiotemporal model. A mixed-effects model with school and subject as random effect was used while adjusting for a priori chosen covariates., Results: An interquartile range (IQR) increment (1.9 µg/m 3 ) in chronic PM 2.5 exposure was associated with a 8.9% (95% CI: -15.4 to -1.9%) shorter TL. In contrast to PM 2.5 , chronic exposure to BC and NO 2 was not associated with TL but recent exposure to BC and NO 2 showed significant inverse associations with TL: an IQR increment in recent exposure to BC (0.9 µg/m 3 ) and NO 2 (10.2 µg/m 3 ) was associated with a 6.2% (95% CI: -10.6 to -1.6%) and 6.4% (95% CI: -11.8 to -0.7%) shorter TL, respectively. Finally, an IQR increment in chronic PM 2.5 exposure was associated with a 12.7% (95% CI: -21.7 to -2.6%) lower mtDNAc. However, no significant associations were seen for NO 2 and BC or for other exposure windows., Conclusion: Chronic exposure to PM 2.5 below the EU threshold was associated with child's shorter buccal TL and lower mtDNAc, while traffic-related pollutants (BC and NO 2 ) showed recent effects on telomere biology. Our data add to the literature on air pollution-induced effects of TL and mtDNAc, two measures part of the core axis of cellular ageing, from early life onwards., (Copyright © 2020. Published by Elsevier Ltd.)

Background: The IGF2 (insulin-like growth factor 2) and H19 gene cluster plays an important role during pregnancy as it promotes both foetal and placental growth. We investigated the association between cord blood DNA methylation status of the IGF2/H19 gene cluster and maternal fine particulate matter exposure during fetal life. To the best of our knowledge, this is the first study investigating the association between prenatal PM 2.5 exposure and newborn DNA methylation of the IGF2/H19., Methods: Cord blood DNA methylation status of IGF2/H19 cluster was measured in 189 mother-newborn pairs from the ENVIRONAGE birth cohort (Flanders, Belgium). We assessed the sex-specific association between residential PM 2.5 exposure during pregnancy and the methylation level of CpG loci mapping to the IGF2/H19 cluster, and identified prenatal vulnerability by investigating susceptible time windows of exposure. We also addressed the biological functionality of DNA methylation level in the gene cluster., Results: Prenatal PM 2.5 exposure was found to have genetic region-specific significant association with IGF2 and H19 during specific gestational weeks. The association was found to be sex-specific in both gene regions. Functionality of the DNA methylation was annotated by the association to fetal growth and cellular pathways., Conclusions: The results of our study provided evidence that prenatal PM 2.5 exposure is associated with DNA methylation in newborns' IGF2/H19. The consequences within the context of fetal development of future phenotyping should be addressed.

Mechanisms underlying adverse birth and later in life health effects from exposure to air pollution during the prenatal period have not been not fully elucidated, especially in the context of mixtures. We assessed the effects of prenatal exposure to mixtures of air pollutants of particulate matter (PM), PM 2.5 , PM 10 , nitrogen oxides, NO 2 , NO x , ultrafine particles (UFP), and oxidative potential (OP) of PM 2.5 on infant birthweight in four European birth cohorts and the mechanistic underpinnings through cross-omics of metabolites and inflammatory proteins. The association between mixtures of air pollutants and birthweight z-scores (standardized for gestational age) was assessed for three different mixture models, using Bayesian machine kernel regression (BKMR). We determined the direct effect for PM 2.5 , PM 10 , NO 2 , and mediation by cross-omic signatures (identified using sparse partial least-squares regression) using causal mediation BKMR models. There was a negative association with birthweight z-scores and exposure to mixtures of air pollutants, where up to -0.21 or approximately a 96 g decrease in birthweight, comparing the 75th percentile to the median level of exposure to the air pollutant mixture could occur. Shifts in birthweight z-scores from prenatal exposure to PM 2.5 , PM 10 , and NO 2 were mediated by molecular mechanisms, represented by cross-omics scores. Interleukin-17 and epidermal growth factor were identified as important inflammatory responses underlyingair pollution-associated shifts in birthweight. Our results signify that by identifying mechanisms through which mixtures of air pollutants operate, the causality of air pollution-associated shifts in birthweight is better supported, substantiating the need for reducing exposure in vulnerable populations.

Background: Iodine is an essential trace element for the production of thyroid hormones, and plays a key role during the gestational period for optimal foetal growth and (neuro-)development. To this day, iodine deficiency remains a global burden. Previous studies indicate that the placenta can store iodine in a concentration-dependent manner and serve as a long-term storage supply, but studies on the determinants of long-term placental iodine load are limited., Methods: The placental iodine concentrations were determined for 462 mother-neonate pairs from the ENVIRONAGE birth cohort (Limburg, Belgium). Sociodemographic and clinical variables were obtained from questionnaires and medical files. Determinants of placental iodine concentration were identified using stepwise multiple regression procedures (p value < 0.15). The biological significance of our findings was investigated by measuring the plasma thyroid hormones in maternal and cord blood of 378 participants., Results: A higher pre-pregnancy BMI, higher gestational weight gain, and alcohol consumption during pregnancy were linked with lower placental iodine storage. Multi-vitamin supplementation during pregnancy and longer gestation were associated with higher levels of placental iodine. Children born during the winter period had on average higher placental iodine levels. Besides, we found a significant positive time trend for placental iodine load over the study period 2013 to 2017. Lastly, we observed positive associations of both the maternal and cord plasma thyroxine concentrations with placental iodine load, emphasizing their biological link., Conclusions: This study identified some determinants likely presenting a risk of reduced iodine storage during the gestational period of life. Future studies should elucidate the effects of lower placental iodine load on neonatal health, and health later in life.

Indoor plants can be used to monitor atmospheric particulates. Here, we report the label-free detection of combustion-derived particles (CDPs) on plants as a monitoring tool for indoor pollution. First, we measured the indoor CDP deposition on Atlantic ivy leaves (Hedera hibernica) using two-photon femtosecond microscopy. Subsequently, to prove its effectiveness for using it as a monitoring tool, ivy plants were placed near five different indoor sources. CDP particle area and number were used as output metrics. CDP values ranged between a median particle area of 0.45 × 10 2 to 1.35 × 10 4 μm 2 , and a median particle number of 0.10 × 10 2 to 1.42 × 10³ particles for the indoor sources: control (greenhouse) < milling machine < indoor smokers < wood stove < gas stove < laser printer. Our findings demonstrate that Atlantic ivy, combined with label-free detection, can be effectively used in indoor atmospheric monitoring studies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hannelore Bové, Maarten B.J. Roeffaers, Marcel Ameloot and Tim S. Nawrot declare competing financial interests. Aspects of the work mentioned in the paper are the subject of a patent application (Method for detecting or quantifying carbon black and/or black carbon particles, US20190025215A1) filed by Hasselt University, Hasselt, Belgium and KU Leuven, Leuven, Belgium. The remaining authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Living in green environments has been associated with various health benefits, but the evidence for positive effects on respiratory health in children is ambiguous., Objective: To investigate if residential exposure to different types of green space is associated with childhood asthma prevalence in Belgium., Methods: Asthma prevalence was estimated from sales data of reimbursed medication for obstructive airway disease (OAD) prescribed to children between 2010 and 2014, aggregated at census tract level (n = 1872) by sex and age group (6-12 and 13-18 years). Generalized log-linear mixed effects models with repeated measures were used to estimate effects of relative covers of forest, grassland and garden in the census tract of the residence on OAD medication sales. Models were adjusted for air pollution (PM 10 ), housing quality and administrative region., Results: Consistent associations between OAD medication sales and relative covers of grassland and garden were observed (unadjusted parameter estimates per IQR increase of relative cover, range across four strata: grassland, β = 0.15-0.17; garden, β = 0.13-0.17). The associations remained significant after adjusting for housing quality and chronic air pollution (adjusted parameter estimates per IQR increase of relative cover, range across four strata: grassland, β = 0.10-0.14; garden, β = 0.07-0.09). There was no association between OAD medication sales and forest cover., Conclusions: Based on aggregated data, we found that living in close proximity to areas with high grass cover (grasslands, but also residential gardens) may negatively impact child respiratory health. Potential allergic and non-allergic mechanisms that underlie this association include elevated exposure to grass pollen and fungi and reduced exposure to environmental biodiversity. Reducing the dominance of grass in public and private green space might be beneficial to reduce the childhood asthma burden and may simultaneously improve the ecological value of urban green space., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited., Methods: To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations., Results: This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns., Conclusions: Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight., Competing Interests: Declaration of competing interest None., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Importance: Neurocognitive functions develop rapidly in early childhood and depend on the intrinsic cooperation between cerebral structures and the circulatory system. The retinal microvasculature can be regarded as a mirror image of the cerebrovascular circulation., Objective: To investigate the association between retinal vessel characteristics and neurological functioning in children aged 4 to 5 years., Design, Setting, and Participants: In this cohort study, mother-child pairs were recruited at birth from February 10, 2010, to June 24, 2014, and renewed consent at their follow-up visit from December 10, 2014, to July 13, 2018. Participants were followed up longitudinally within the prospective Environmental Influence on Aging in Early Life birth cohort. A total of 251 children underwent assessment for this study. Data were analyzed from July 17 to October 30, 2019., Main Outcomes and Measures: Retinal vascular diameters, the central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), vessel tortuosity, and fractal dimensions were determined. Attention and psychomotor speed, visuospatial working memory, and short-term visual recognition memory were assessed by the Cambridge Neuropsychological Test Automated Battery, including the following tasks: Motor Screening (MOT), Big/Little Circle (BLC), Spatial Span (SSP), and Delayed Matching to Sample (DMS)., Results: Among the 251 children included in the assessment (135 girls [53.8%]; mean [SD] age, 4.5 [0.4] years), for every 1-SD widening in CRVE, the children performed relatively 2.74% (95% CI, -0.12 to 5.49; P = .06) slower on the MOT test, had 1.76% (95% CI, -3.53% to -0.04%; P = .04) fewer correct DMS assessments in total, and made 2.94% (95% CI, 0.39 to 5.29; P = .02) more errors given a previous correct answer in the DMS task on multiple linear regression modeling. For every 1-SD widening in CRAE, the total percentage of errors and errors given previous correct answers in the DMS task increased 1.44% (95% CI, -3.25% to 0.29%; P = .09) and 2.30% (95% CI, -0.14% to 4.61%; P = .07), respectively. A 1-SD higher vessel tortuosity showed a 4.32% relative increase in latency in DMS task performance (95% CI, -0.48% to 9.12%; P = .07). Retinal vessel characteristics were not associated with BLC and SSP test outcomes., Conclusions and Relevance: These findings suggest that children's microvascular phenotypes are associated with short-term memory and that changes in the retinal microvasculature may reflect neurological development during early childhood.

Background: Particulate matter exposure during in utero life may entail adverse health outcomes later in life. The microvasculature undergoes extensive, organ-specific prenatal maturation. A growing body of evidence shows that cardiovascular disease in adulthood is rooted in a dysfunctional fetal and perinatal development, in particular that of the microcirculation. We investigate whether prenatal or postnatal exposure to PM 2.5 (particulate matter with a diameter ≤ 2.5 μm) or NO 2 is related to microvascular traits in children between the age of four and six., Methods: We measured the retinal microvascular diameters, the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE), and the vessel curvature by means of the tortuosity index (TI) in young children (mean [SD] age 4.6 [0.4] years), followed longitudinally within the ENVIRONAGE birth cohort. We modeled daily prenatal and postnatal PM 2.5 and NO 2 exposure levels for each participant's home address using a high-resolution spatiotemporal model., Results: An interquartile range (IQR) increase in PM 2.5 exposure during the entire pregnancy was associated with a 3.85-μm (95% CI, 0.10 to 7.60; p = 0.04) widening of the CRVE and a 2.87-μm (95% CI, 0.12 to 5.62; p = 0.04) widening of the CRAE. For prenatal NO 2 exposure, an IQR increase was found to widen the CRVE with 4.03 μm (95% CI, 0.44 to 7.63; p = 0.03) and the CRAE with 2.92 μm (95% CI, 0.29 to 5.56; p = 0.03). Furthermore, a higher TI score was associated with higher prenatal NO 2 exposure. We observed a postnatal effect of short-term PM 2.5 exposure on the CRAE and a childhood NO 2 exposure effect on both the CRVE and CRAE., Conclusions: Our results link prenatal and postnatal air pollution exposure with changes in a child's microvascular traits as a fundamental novel mechanism to explain the developmental origin of cardiovascular disease.