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Background: Nephron number variability may hold significance in the Developmental Origins of Health and Disease hypothesis. We explore the impact of gestational particulate pollution exposure on cord blood cystatin C, a marker for glomerular function, as an indicator for glomerular health at birth., Methods: From February 2010 onwards, the ENVIRONAGE cohort includes over 2200 mothers giving birth at the East-Limburg hospital in Genk, Belgium. Mothers without planned caesarean section who are able to fill out a Dutch questionnaire are eligible. Here, we evaluated cord blood cystatin C levels from 1484 mother-child pairs participating in the ENVIRONAGE cohort. We employed multiple linear regression models and distributed lag models to assess the association between cord blood cystatin C and gestational particulate air pollution exposure., Findings: Average ± SD levels of cord blood cystatin C levels amounted to 2.16 ± 0.35 mg/L. Adjusting for covariates, every 0.5 μg/m³ and 5 μg/m³ increment in gestational exposure to black carbon (BC) and fine particulate matter (PM 2.5 ) corresponded to increases of 0.04 mg/L (95% CI 0.01-0.07) and 0.07 mg/L (95% CI 0.03-0.11) in cord blood cystatin C levels (p < 0.01), respectively. Third-trimester exposure showed similar associations, with a 0.04 mg/L (95% CI 0.00-0.08) and 0.06 mg/L (95% CI 0.04-0.09) increase for BC and PM 2.5 (p < 0.02). No significant associations were observed when considering only the first and second trimester exposure., Interpretation: Our findings indicate that particulate air pollution during the entire pregnancy, with the strongest effect sizes from week 27 onwards, may affect newborn kidney function, with potential long-term implications for later health., Funding: Special Research Fund (Bijzonder Onderzoeksfonds, BOF), Flemish Scientific Research Fund (Fonds Wetenschappelijk Onderzoek, FWO), and Methusalem., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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: 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).)

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: 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.)

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).)

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: 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.)

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: 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: 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.

According to the "Developmental Origins of Health and Disease" (DOHaD) concept, the early-life environment is a critical period for fetal programming. Given the epidemiological evidence that air pollution exposure during pregnancy adversely affects newborn outcomes such as birth weight and preterm birth, there is a need to pay attention to underlying modes of action to better understand not only these air pollution-induced early health effects but also its later-life consequences. In this review, we give an overview of air pollution-induced placental molecular alterations observed in the ENVIRONAGE birth cohort and evaluate the existing evidence. In general, we showed that prenatal exposure to air pollution is associated with nitrosative stress and epigenetic alterations in the placenta. Adversely affected CpG targets were involved in cellular processes including DNA repair, circadian rhythm, and energy metabolism. For miRNA expression, specific air pollution exposure windows were associated with altered miR-20a, miR-21, miR-146a, and miR-222 expression. Early-life aging markers including telomere length and mitochondrial DNA content are associated with air pollution exposure during pregnancy. Previously, we proposed the air pollution-induced telomere-mitochondrial aging hypothesis with a direct link between telomeres and mitochondria. Here, we extend this view with a potential co-interaction of different biological mechanisms on the level of placental oxidative stress, epigenetics, aging, and energy metabolism. Investigating the placenta is an opportunity for future research as it may help to understand the fundamental biology underpinning the DOHaD concept through the interactions between the underlying modes of action, prenatal environment, and disease risk in later life. To prevent lasting consequences from early-life exposures of air pollution, policy makers should get a basic understanding of biomolecular consequences and transgenerational risks.

Introduction: Limited evidence suggests that epigenetic mechanisms may partially mediate the adverse effects of air pollution on health. Our aims were to identify new genomic loci showing differential DNA methylation associated with long-term exposure to air pollution and to replicate loci previously identified in other studies., Methods: A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. DNA methylation was assessed using the Infinium HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured according to the ESCAPE protocol. A systematic review was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air pollution in previous studies and we screened for them in the discovery study., Results: In the discovery stage of the epigenome-wide association study, 81 unique CpGs were associated with air pollution (p-value <10 -5 ) but none of them were validated in the replication sample. Furthermore, we identified 15 CpGs in the systematic review showing differential methylation with a p-value fulfilling the Bonferroni criteria and 1673 CpGs fulfilling the false discovery rate criteria, all of which were related to PM 2.5 or NO 2 . None of them was replicated in the discovery study, in which the top hits were located in an intergenic region on chromosome 1 (cg10893043, p-value = 6.79·10 -5 ) and in the LRRC45 and PXK genes (cg05088605, p-value = 2.15·10 -04 ; cg16560256, p-value = 2.23·10 -04 )., Conclusions: Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated. Continued efforts to test this potential association are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Studies investigating short-term exposure to ambient air pollution and heart rate variability (HRV) suggest that particulate matter (PM) exposure is associated with reductions in measures of HRV. Mitochondria are sensitive to PM exposure and may represent a biologically relevant underlying mechanism. However, evidence in children is lacking., Objectives: Here we examine whether PM has an influence on children's HRV and evaluate whether mitochondrial DNA content (mtDNAc) reflects individual susceptibility., Methods: Within a panel study in primary school children (aged 9-12 years), we measured HRV in a subset of 60 children on three different days during school-time using four indicators: normal-to-normal intervals (SDNN), square root of mean squared difference of normal-to-normal intervals (rMSSD), high frequency (HF), and low frequency (LF). This resulted in a total number of 150 visits (median number of visits per child: 2.5/child). MtDNAc was measured using qPCR in buccal cells. We measured recent PM exposure at the school. Residential 24-hour mean exposure to PM was modelled with a high resolution spatial temporal model. Mixed-effects models were used to estimate the association between HRV and recent PM exposure and potential effect-modification by mtDNAc., Results: Children were on average [SD] 9.9 [1.2] years and comprised 39 girls. Median [25th-75th] recent outdoor PM 2.5 and PM 10 exposure at school was 6.20 [2.8-12.8] μg/m 3 and 29.3 [24.7-42.0] μg/m 3 , respectively. In children with low mtDNAc (25th percentile), we observed for each 10 μg/m 3 increment in recent PM 2.5 exposure a lowering in the LF parameter with 9.76% (95% CI: -16.9 to -1.99%, p = 0.02; p int  = 0.007). Children with high mtDNAc did not show this association. For PM 10 exposure, we observed an inverse association with three HRV indicators in children with low mtDNAc: -2.24% (95% CI: -4.27 to -0.16%; p = 0.04; p int  = 0.02) for SDNN, -5.67% (95% CI: -10.5 to -0.59%; p = 0.03; p int  = 0.04) for HF and -6.64% (95% CI: -10.7 to -2.38%; p = 0.003; p int  = 0.005) for LF., Conclusions: HRV is inversely associated with recent PM air pollution, especially in children with low mtDNAc. Our data revealed that mtDNAc determines susceptibility to adverse autonomic effects of recent PM exposure in children., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose of Review: This systematic review evaluated existing evidence linking air pollution exposure in humans to major epigenetic mechanisms: DNA methylation, microRNAs, long noncoding RNAs, and chromatin regulation., Recent Findings: Eighty-two manuscripts were eligible, most of which were observational (85%), conducted in adults (66%) and based on DNA methylation (79%). Most observational studies, except panel, demonstrated modest effects of air pollution on the methylome. Panel and experimental studies revealed a relatively large number of significant methylome alterations, though based on smaller sample sizes. Particulate matter levels were positively associated in several studies with global or LINE-1 hypomethylation, a hallmark of several diseases, and with decondensed chromatin structure. Several air pollution species altered the DNA methylation clock, inducing accelerated biological aging. The causal nature of identified associations is not clear, however, especially that most originate from countries with low air pollution levels. Existing evidence, gaps, and perspectives are highlighted herein.

Air pollution has been classified as carcinogenic to humans. However, to date little is known about the relevance for cancers of the stomach and upper aerodigestive tract (UADT). We investigated the association of long-term exposure to ambient air pollution with incidence of gastric and UADT cancer in 11 European cohorts. Air pollution exposure was assigned by land-use regression models for particulate matter (PM) below 10 µm (PM 10 ), below 2.5 µm (PM 2.5 ), between 2.5 and 10 µm (PM coarse ), PM 2.5 absorbance and nitrogen oxides (NO 2 and NO X ) as well as approximated by traffic indicators. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses. Combined estimates were determined with random effects meta-analyses. During average follow-up of 14.1 years of 305,551 individuals, 744 incident cases of gastric cancer and 933 of UADT cancer occurred. The hazard ratio for an increase of 5 µg/m 3 of PM 2.5 was 1.38 (95% CI 0.99; 1.92) for gastric and 1.05 (95% CI 0.62; 1.77) for UADT cancers. No associations were found for any of the other exposures considered. Adjustment for additional confounders and restriction to study participants with stable addresses did not influence markedly the effect estimate for PM 2.5 and gastric cancer. Higher estimated risks of gastric cancer associated with PM 2.5 was found in men (HR 1.98 [1.30; 3.01]) as compared to women (HR 0.85 [0.5; 1.45]). This large multicentre cohort study shows an association between long-term exposure to PM 2.5 and gastric cancer, but not UADT cancers, suggesting that air pollution may contribute to gastric cancer risk., (© 2018 UICC.)

Background: Fetal development is a crucial window of susceptibility in which exposure-related alterations can be induced on the molecular level, leading to potential changes in metabolism and development. The placenta serves as a gatekeeper between mother and fetus, and is in contact with environmental stressors throughout pregnancy. This makes the placenta as a temporary organ an informative non-invasive matrix suitable to investigate omics-related aberrations in association with in utero exposures such as ambient air pollution., Objectives: To summarize and discuss the current evidence and define the gaps of knowledge concerning human placental -omics markers in association with prenatal exposure to ambient air pollution., Methods: Two investigators independently searched the PubMed, ScienceDirect, and Scopus databases to identify all studies published until January 2017 with an emphasis on epidemiological research on prenatal exposure to ambient air pollution and the effect on placental -omics signatures., Results: From the initial 386 articles, 25 were retained following an a priori set inclusion and exclusion criteria. We identified eleven studies on the genome, two on the transcriptome, five on the epigenome, five on the proteome category, one study with both genomic and proteomic topics, and one study with both genomic and transcriptomic topics. Six studies discussed the triple relationship between exposure to air pollution during pregnancy, the associated placental -omics marker(s), and the potential effect on disease development later in life. So far, no metabolomic or exposomic data discussing associations between the placenta and prenatal exposure to air pollution have been published., Conclusions: Integration of placental biomarkers in an environmental epidemiological context enables researchers to address fundamental questions essential in unraveling the fetal origin of disease and helps to better define the pregnancy exposome of air pollution., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Ambient air pollution contains low concentrations of carcinogens implicated in the etiology of urinary bladder cancer (BC). Little is known about whether exposure to air pollution influences BC in the general population., Objective: To evaluate the association between long-term exposure to ambient air pollution and BC incidence., Design, Setting, and Participants: We obtained data from 15 population-based cohorts enrolled between 1985 and 2005 in eight European countries (N=303431; mean follow-up 14.1 yr). We estimated exposure to nitrogen oxides (NO 2 and NO x ), particulate matter (PM) with diameter <10μm (PM 10 ), <2.5μm (PM 2.5 ), between 2.5 and 10μm (PM 2.5-10 ), PM 2.5 (soot), elemental constituents of PM, organic carbon, and traffic density at baseline home addresses using standardized land-use regression models from the European Study of Cohorts for Air Pollution Effects project.absorbance (soot), elemental constituents of PM, organic carbon, and traffic density at baseline home addresses using standardized land-use regression models from the European Study of Cohorts for Air Pollution Effects project., Outcome Measurements and Statistical Analysis: We used Cox proportional-hazards models with adjustment for potential confounders for cohort-specific analyses and meta-analyses to estimate summary hazard ratios (HRs) for BC incidence., Results and Limitations: During follow-up, 943 incident BC cases were diagnosed. In the meta-analysis, none of the exposures were associated with BC risk. The summary HRs associated with a 10-μg/m 3 increase in NO 2 and 5-μg/m 3 increase in PM 2.5 were 0.98 (95% confidence interval [CI] 0.89-1.08) and 0.86 (95% CI 0.63-1.18), respectively. Limitations include the lack of information about lifetime exposure., Conclusions: There was no evidence of an association between exposure to outdoor air pollution levels at place of residence and risk of BC., Patient Summary: We assessed the link between outdoor air pollution at place of residence and bladder cancer using the largest study population to date and extensive assessment of exposure and comprehensive data on personal risk factors such as smoking. We found no association between the levels of outdoor air pollution at place of residence and bladder cancer risk., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes. This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO 2 , NO x , PM 2.5 , PM coarse , PM 10 , PM 2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available. Exposure to NO 2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO 2 and NO x . Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO 2 and 9 for NO x mainly related to the immune system and its regulation. Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO 2 and NO x . Functional differences in the immune system were suggested by transcriptome analyses., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Epidemiological evidence on the association between ambient air pollution and breast cancer risk is inconsistent., Objective: We examined the association between long-term exposure to ambient air pollution and incidence of postmenopausal breast cancer in European women., Methods: In 15 cohorts from nine European countries, individual estimates of air pollution levels at the residence were estimated by standardized land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE) and Transport related Air Pollution and Health impacts – Integrated Methodologies for Assessing Particulate Matter (TRANSPHORM) projects: particulate matter (PM) ≤2.5μm, ≤10μm, and 2.5–10μm in diameter (PM 2.5 , PM 10 , and PM coarse , respectively); PM 2.5 absorbance; nitrogen oxides (NO 2 and NO x ); traffic intensity; and elemental composition of PM. We estimated cohort-specific associations between breast cancer and air pollutants using Cox regression models, adjusting for major lifestyle risk factors, and pooled cohort-specific estimates using random-effects meta-analyses., Results: Of 74,750 postmenopausal women included in the study, 3,612 developed breast cancer during 991,353 person-years of follow-up. We found positive and statistically insignificant associations between breast cancer and PM 2.5 {hazard ratio (HR)=1.08 [95% confidence interval (CI): 0.77, 1.51] per 5 μg/m 3 }, PM 10 [1.07 (95% CI: 0.89, 1.30) per 10 μg/m 3 ], PM coarse [1.20 (95% CI: 0.96, 1.49 per 5 μg/m 3 ], and NO 2 [1.02 (95% CI: 0.98, 1.07 per 10 μg/m 3 ], and a statistically significant association with NO x [1.04 (95% CI: 1.00, 1.08) per 20 μg/m 3 , p =0.04]., Conclusions: We found suggestive evidence of an association between ambient air pollution and incidence of postmenopausal breast cancer in European women. https://doi.org/10.1289/EHP1742.

Introduction: Cardio-metabolic risk factors including insulin levels are at young age barely perceived as harmful, but over time these risk factors may track and lead to higher risk of metabolic syndrome. Studies showed that exposure to air pollution is associated with an increased risk of insulin resistance in childhood. We determined whether the origin of type 2 diabetes can be found in the early childhood by examining the levels of insulin in the neonatal cord blood and whether this can be considered as a disease marker for later life., Methods: In the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort, we recruited 620 mother-infant pairs between February 2nd 2010 until August 12th 2014 at the East-Limburg Hospital in Genk, Belgium. We investigated in 590 newborns the association between cord plasma insulin levels and exposure to particulate matter (PM 2.5 and PM 10 ) and nitrogen dioxide (NO 2 ) in various exposure windows during pregnancy. Trimester-specific air pollutant exposure levels were estimated for each mother's home address using a spatiotemporal model., Results: Cord plasma insulin levels averaged 33.1pmol/L (25-75th percentile: 20.1-53.5), while PM 2.5 exposure during pregnancy averaged (SD) 13.7μg/m 3 (2.4). Independent of maternal age, newborn's sex, birth weight, gestational age, parity, early-pregnancy BMI, ethnicity, smoking status, time of the day, maternal education, time of delivery, and season of delivery, cord plasma insulin levels increased with 15.8% (95% CI 7.8 to 24.4, p<0.0001) for each SD increment in PM 2.5 levels during the entire pregnancy and was most pronounced in the 2nd trimester (13.1%, 95% CI 3.4 to 23.7, p=0.007) of pregnancy. The results for PM 10 exposure were similar with those of PM 2.5 exposure but we did not observe an association between cord blood insulin levels and NO 2 exposure., Conclusions: Exposure to particulate air pollution during pregnancy is associated with increased levels of cord plasma insulin at birth. The public health relevance of this association is demonstrated by the fact that a 2.4μg/m 3 (SD) increase in PM 2.5 during pregnancy on cord plasma insulin levels corresponds to the effect-size of a 9kg/m 2 higher early-pregnancy BMI on cord plasma. Particulate air pollution induced changes in cord plasma insulin levels during early life and might be a risk factor in the development of metabolic disease, such as glucose intolerance or type 2 diabetes, later in life., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Particulate matter (PM) exposure leads to premature death, mainly due to respiratory and cardiovascular diseases., Objectives: Identification of transcriptomic biomarkers of air pollution exposure and effect in a healthy adult population., Methods: Microarray analyses were performed in 98 healthy volunteers (48 men, 50 women). The expression of eight sex-specific candidate biomarker genes (significantly associated with PM 10 in the discovery cohort and with a reported link to air pollution-related disease) was measured with qPCR in an independent validation cohort (75 men, 94 women). Pathway analysis was performed using Gene Set Enrichment Analysis. Average daily PM 2.5 and PM 10 exposures over 2-years were estimated for each participant's residential address using spatiotemporal interpolation in combination with a dispersion model., Results: Average long-term PM 10 was 25.9 (± 5.4) and 23.7 (± 2.3) μg/m 3 in the discovery and validation cohorts, respectively. In discovery analysis, associations between PM 10 and the expression of individual genes differed by sex. In the validation cohort, long-term PM 10 was associated with the expression of DNAJB5 and EAPP in men and ARHGAP4 ( p = 0.053) in women. AKAP6 and LIMK1 were significantly associated with PM 10 in women, although associations differed in direction between the discovery and validation cohorts. Expression of the eight candidate genes in the discovery cohort differentiated between validation cohort participants with high versus low PM 10 exposure (area under the receiver operating curve = 0.92; 95% CI: 0.85, 1.00; p = 0.0002 in men, 0.86; 95% CI: 0.76, 0.96; p = 0.004 in women)., Conclusions: Expression of the sex-specific candidate genes identified in the discovery population predicted PM 10 exposure in an independent cohort of adults from the same area. Confirmation in other populations may further support this as a new approach for exposure assessment, and may contribute to the discovery of molecular mechanisms for PM-induced health effects.

Background: Telomere length and mitochondrial DNA (mtDNA) content are markers of aging and aging-related diseases. There is inconclusive evidence concerning the mechanistic effects of airborne particulate matter (PM) exposure on biomolecular markers of aging., Objective: The present study examines the association between short- and long-term PM exposure with telomere length and mtDNA content in the elderly and investigates to what extent this association is mediated by expression of genes playing a role in the telomere-mitochondrial axis of aging., Methods: Among 166 nonsmoking elderly participants, we used qPCR to measure telomere length and mtDNA content in leukocytes and RNA from whole blood to measure expression of SIRT1, TP53, PPARGC1A, PPARGC1B, NRF1, and NFE2L2. Associations between PM exposure and markers of aging were estimated using multivariable linear regression models adjusted for sex, age, BMI, socioeconomic status, statin use, past smoking status, white blood cell count, and percentage of neutrophils. Mediation analysis was performed to explore the role of age-related markers between the association of PM exposure and outcome. Annual PM2.5 exposure was calculated for each participant's home address using a high-resolution spatial-temporal interpolation model., Results: Annual PM2.5 concentrations ranged from 15 to 23 μg/m3. A 5-μg/m3 increment in annual PM2.5 concentration was associated with a relative decrease of 16.8% (95% CI: -26.0%, -7.4%, p = 0.0005) in telomere length and a relative decrease of 25.7% (95% CI: -35.2%, -16.2%, p < 0.0001) in mtDNA content. Assuming causality, results of the mediation analysis indicated that SIRT1 mediated 19.5% and 22.5% of the estimated effect of PM2.5 exposure on telomere length and mtDNA content, respectively., Conclusions: Our findings suggest that the estimated effects of PM2.5 exposure on the telomere-mitochondrial axis of aging may play an important role in chronic health effects of PM2.5., Citation: Pieters N, Janssen BG, Dewitte H, Cox B, Cuypers A, Lefebvre W, Smeets K, Vanpoucke C, Plusquin M, Nawrot TS. 2016. Biomolecular markers within the core axis of aging and particulate air pollution exposure in the elderly: a cross-sectional study. Environ Health Perspect 124:943-950; http://dx.doi.org/10.1289/ehp.1509728.

Background: Ultrafine particles (UFP) may contribute to the cardiovascular effects of particulate air pollution, partly because of their relatively efficient alveolar deposition., Objective: In this study, we assessed associations between blood pressure and short-term exposure to air pollution in a population of schoolchildren., Methods: In 130 children (6-12 years of age), blood pressure was determined during two periods (spring and fall 2011). We used mixed models to study the association between blood pressure and ambient concentrations of particulate matter and ultrafine particles measured in the schools' playground., Results: Independent of sex, age, height, and weight of the child, parental education, neighborhood socioeconomic status, fish consumption, heart rate, school, day of the week, season, wind speed, relative humidity, and temperature on the morning of examination, an interquartile range (860 particles/cm3) increase in nano-sized UFP fraction (20-30 nm) was associated with a 6.35 mmHg (95% CI: 1.56, 11.14; p = 0.01) increase in systolic blood pressure. For the total UFP fraction, systolic blood pressure was 0.79 mmHg (95% CI: 0.07, 1.51; p = 0.03) higher, but no effects on systolic blood pressure were found for the nano-sized fractions with a diameter > 100 nm, nor PM2.5, PMcoarse, and PM10. Diastolic blood pressure was not associated with any of the studied particulate mass fractions., Conclusion: Children attending school on days with higher UFP concentrations (diameter < 100 nm) had higher systolic blood pressure. The association was dependent on UFP size, and there was no association with the PM2.5 mass concentration.