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Objectives Lead exposure causes neurocognitive dysfunction in children, but its association with neurocognition in adults at current occupational exposure levels is uncertain mainly due to the lack of longitudinal studies. In the Study for Promotion of Health in Recycling Lead (NCT02243904), we assessed the two-year responses of neurocognitive function among workers without previous known occupational exposure newly hired at lead recycling plants. Methods Workers completed the digit-symbol test (DST) and Stroop test (ST) at baseline and annual follow-up visits. Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 mu g/dL). Statistical methods included multivariable-adjusted mixed models with participants modelled as random effect. Results DST was administered to 260 participants (11.9% women; 46.9%/45.0% whites/Hispanics; mean age 29.4 years) and ST to 168 participants. Geometric means were 3.97 and 4.13 mu g/dL for baseline BL, and 3.30 and 3.44 for the last-follow-up-to-baseline BL ratio in DST and ST cohorts, respectively. In partially adjusted models, a doubling of the BL ratio was associated with a 0.66% [95% confidence interval (CI) 0.03-1.30%; P=0.040] increase in latency time (DST) and a 0.35% (95% CI -1.63-1.63%; P=0.59) decrease in the inference effect (ST). In fully adjusted models, none of the associations of the changes in the DST and ST test results with the blood lead changes reached statistical significance (P=0.12). Conclusions An over 3-fold increase in blood lead over two years of occupational exposure was not associated with a relevant decline in cognitive performance. The International Lead Association (www.ila-lead.org) provided an unrestricted grant to the Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, partially supporting database management and statistical analysis. The non-profit research institute Alliance for the Promotion of Preventive Medicine (www.appremed.org) received a grant from OMRON Healthcare Co. Ltd., Kyoto, Japan. The funding source had no role in the study design; in the collection, analysis, and interpretation of the data; or in the writing of the report. The corresponding author had full access to all data and had the final responsibility for the decision to submit for publication. Staessen, JA (corresponding author), Res Inst Assoc Promot Prevent Med, Leopoldstr 59, BE-2800 Mechelen, Belgium. jan.staessen@appremed.org

Background: Residential green space may improve human health, for example by promoting physical activity and by reducing stress. Conversely, residential green space may increase stress by emitting aeroallergens and exacerbating allergic disease. Here we examine impacts of exposure to residential green space on distress in the susceptible subpopulation of adults sensitized to tree pollen allergens. Methods: In a panel study of 88 tree pollen allergy patients we analyzed self-reported mental health (GHQ-12), perceived presence of allergenic trees (hazel, alder, birch) near the residence and residential green space area within 1 km distance [high (>= 3 m) and low (< 3 m) green]. Results were adjusted for patients' background data (gender, age, BMI, smoking status, physical activity, commuting distance, education level, allergy medication use and chronic respiratory problems) and compared with distress in the general population (N = 2467). Results: Short-term distress [mean GHQ-12 score 2.1 (95% confidence interval 1.5-2.7)] was higher in the study population than in the general population [1.5 (1.4-1.7)]. Residential green space had protective effects against short-term distress [high green, per combined surface area of 10 ha: adjusted odds ratio OR = 0.94 (95% confidence interval 0.90-0.99); low green, per 10 ha: OR = 0.85 (0.78-0.93)]. However, distress was higher in patients who reported perceived presence of allergenic trees near their residence [present vs. absent: OR = 2.04 (1.36-3.07)]. Conclusions: Perceived presence of allergenic tree species in the neighbourhood of the residence of tree pollen allergy patients modulates the protective effect of residential green space against distress during the airborne tree pollen season. The RespirIT study has been supported by a project grant from the Belgian Science Policy Office BELSPO (grant nr. BR/154/A1/RespirIT). The GHQ-12 questionnaire was used under license from GL Assessment Ltd. Aerts, R (reprint author), Sciensano, Juliette Wytsmanstr 14, BE-1050 Brussels, Belgium. raf.aerts@sciensano.be

In epidemiological studies, assessment of long term exposure to air pollution is often estimated using air pollution measurements at fixed monitoring stations, and interpolated to the residence of survey participants through Geographical Information Systems (GIS). However, obtaining georeferenced address data from national registries requires a long and cumbersome administrative procedure, since this kind of personal data is protected by privacy regulations. This paper aims to assess whether information collected in health interview surveys, including air pollution annoyance, could be used to build prediction models for assessing individual long term exposure to air pollution, removing the need for data on personal residence address.Analyses were carried out based on data from the Belgian Health Interview Survey (BHIS) 2013 linked to GISmodelled air pollution exposure at the residence place of participants older than 15 years (n = 9347). First, univariate linear regressions were performed to assess the relationship between air pollution annoyance and modelled exposure to each air pollutant. Secondly, a multivariable linear regression was performed for each air pollutant based on a set of variables selected with elastic net cross-validation, including variables related to environmental annoyance, socio-economic and health status of participants. Finally, the performance of the models to classify individuals in three levels of exposure was assessed by means of a confusion matrix.Our results suggest a limited validity of self-reported air pollution annoyance as a direct proxy for air pollution exposure and a weak contribution of environmental annoyance variables in prediction models. Models using variables related to the socio-economic status, region, urban level and environmental annoyance allow to predict individual air pollution exposure with a percentage of error ranging from 8% to 18%. Although these models do not provide very accurate predictions in terms of absolute exposure to air pollution, they do allow to classify individuals in groups of relative exposure levels, ranking participants from low over medium to high air pollution exposure. This model represents a rapid assessment tool to identify groups within the BHIS participants undergoing the highest levels of environmental stress.

Particular matter (PM) exposure is a big hazard for public health, especially for children. Serum CC16 is a wellknown biomarker of respiratory health. Urinary CC16 (U-CC16) can be a noninvasive alternative, albeit requiring adequate adjustment for renal handling. Moreover, the SNP CC16 G38A influences CC16 levels. This study aimed to monitor the effect of short-term PM exposure on CC16 levels, measured noninvasively in schoolchildren, using an integrative approach. We used a selection of urine and buccal DNA samples from 86 children stored in an existing biobank. Using a multiple reaction monitoring method, we measured U-CC16, as well as RBP4 (retinol binding protein 4) and beta 2M (beta-2-microglobulin), required for adjustment. Buccal DNA samples were used for CC16 G38A genotyping. Linear mixed-effects models were used to find relevant associations between U-CC16 and previously obtained data from recent daily PM = 2.5 or 10 mu m exposure (PM2.5, PM10) modeled at the child's residence. Our study showed that exposure to low PM at the child's residence (median levels 18.9 mu g/m(3) (PM2.5) and 23.6 mu g/m(3) (PM10)) one day before sampling had an effect on the covariates-adjusted U-CC16 levels. This effect was dependent on the CC16 G38A genotype, due to its strong interaction with the association between PM levels and covariates-adjusted U-CC16 (P = 0.024 (PM2.5); P = 0.061 (PM10)). Only children carrying the 38GG genotype showed an increase of covariates-adjusted U-CC16, measured 24h after exposure, with increasing PM2.5 and PM10 (beta = 0.332; 95% CI: 0.110 to 0.554 and beta = 0.372; 95% CI: 0.101 to 0.643, respectively). To the best of our knowledge, this is the first study using an integrative approach to investigate short-term PM exposure of children, using urine to detect early signs of pulmonary damage, and taking into account important determinants such as the genetic background and adequate adjustment of the measured biomarker in urine. The authors would like to thank all collaborators from UHasselt who were implicated in the conduction of the initial COGNAC study, including the set-up, the sampling, the examinations and measurements, and of which samples were used in this study.

Particle transfer across the placenta has been suggested but to date, no direct evidence in real-life, human context exists. Here we report the presence of black carbon (BC) particles as part of combustion-derived particulate matter in human placentae using white-light generation under femtosecond pulsed illumination. BC is identified in all screened placentae, with an average (SD) particle count of 0.95 × 10

Particular matter (PM) exposure is a big hazard for public health, especially for children. Serum CC16 is a well-known biomarker of respiratory health. Urinary CC16 (U-CC16) can be a noninvasive alternative, albeit requiring adequate adjustment for renal handling. Moreover, the SNP CC16 G38A influences CC16 levels. This study aimed to monitor the effect of short-term PM exposure on CC16 levels, measured noninvasively in schoolchildren, using an integrative approach. We used a selection of urine and buccal DNA samples from 86 children stored in an existing biobank. Using a multiple reaction monitoring method, we measured U-CC16, as well as RBP4 (retinol binding protein 4) and β2M (beta-2-microglobulin), required for adjustment. Buccal DNA samples were used for CC16 G38A genotyping. Linear mixed-effects models were used to find relevant associations between U-CC16 and previously obtained data from recent daily PM ≤ 2.5 or 10 μm exposure (PM

Mitochondria are known to respond to environmental stressors but whether green space is associated with mitochondrial abundance is unexplored. Furthermore, as exposures may affect health from early life onwards, we here evaluate if residential green space is associated with mitochondria DNA content (mtDNAc) in children.In primary schoolchildren (COGNAC study), between 2012 and 2014, buccal mtDNAc was repeatedly (three times) assessed using qPCR. Surrounding low (3m), high (≥3m) and total (sum of low and high) green space within different radii (100m-1000m) from the residence and distance to the nearest large green space (0.5ha) were estimated using a remote sensing derived map. Given the repeated measures design, we applied a mixed-effects model with school and subject as random effect while adjusting for a priori chosen fixed covariates.mtDNAc was assessed in 246 children with a total of 436 measurements (mean age 10.3 years). Within a 1000m radius around the residential address, an IQR increment in low (11.0%), high (9.5%), and total (13.9%) green space was associated with a respectively 15.2% (95% CI: 7.2%-23.7%), 10.8% (95% CI: 4.5%-17.5%), and 13.4% (95% CI: 7.4%-19.7%) higher mtDNAc. Conversely, an IQR increment (11.6%) in agricultural area in the same radius was associated with a -3.4% (95% CI: 6.7% to -0.1%) lower mtDNAc. Finally, a doubling in distance to large green space was associated with a -5.2% (95% CI: 7.9 to -2.4%) lower mtDNAc.To our knowledge, this is the first study evaluating associations between residential surrounding green space and mtDNAc in children. Our results showed that green space was associated with a higher mtDNAc in children, which indicates the importance of the early life environment. To what extent these findings contribute to later life health effects should be further examined.

Particle transfer across the placenta has been suggested but to date, no direct evidence in real-life, human context exists. Here we report the presence of black carbon (BC) particles as part of combustion-derived particulate matter in human placentae using white-light generation under femtosecond pulsed illumination. BC is identified in all screened placentae, with an average (SD) particle count of 0.95 × 104 (0.66 × 104) and 2.09 × 104 (0.9 × 104) particles per mm3 for low and high exposed mothers, respectively. Furthermore, the placental BC load is positively associated with mothers’ residential BC exposure during pregnancy (0.63–2.42 µg per m3). Our finding that BC particles accumulate on the fetal side of the placenta suggests that ambient particulates could be transported towards the fetus and represents a potential mechanism explaining the detrimental health effects of pollution from early life onwards., Exposure to air pollution during pregnancy has been associated with impaired birth outcomes. Here, Bové et al. report evidence of black carbon particle deposition on the fetal side of human placentae, including at early stages of pregnancy, suggesting air pollution could affect birth outcome through direct effects on the fetus.

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 PM2.5 and PM10 exposure at school was 6.20 [2.8–12.8] μg/m3 and 29.3 [24.7–42.0] μg/m3, respectively. In children with low mtDNAc (25th percentile), we observed for each 10 μg/m3 increment in recent PM2.5 exposure a lowering in the LF parameter with 9.76% (95% CI: −16.9 to −1.99%, p = 0.02; pint = 0.007). Children with high mtDNAc did not show this association. For PM10 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; pint = 0.02) for SDNN, −5.67% (95% CI: −10.5 to −0.59%; p = 0.03; pint = 0.04) for HF and −6.64% (95% CI: −10.7 to −2.38%; p = 0.003; pint = 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., Highlights • Particulate matter (PM) exposure is associated with lower heart rate variability (HRV). • We found an inverse HRV-PM association in children with low mtDNA content. • The association was not observed in children with high mtDNA content. • Mitochondrial DNA determines susceptibility to adverse autonomic effects of PM.

Objectives Higher than contemporary exposure levels and advanced age of study participants have limited the interpretation of previous studies relating neurocognitive function to lead exposure. We reassessed this association in young American men prior to chronic occupational exposure at lead recycling plants, using baseline measurements of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods We administered the Stroop test (ST) and the digit-symbol test (DST) to 339 men (mean age, 28.6 years; participation rate 82.7%). Whole blood lead (BL) was determined by inductively coupled plasma mass spectrometry and related ST and DST test results using multivariable-adjusted regression. Results Average values were 4.26 mu g/dL for BL, 1624 ms and 1474 ms for mean reaction time in incongruent and congruent ST trials, and 109 sec for mean total latency in DST. The number of participants with fully correct answers amounted to 281 (82.9%) and 334 (98.5%) in incongruent and congruent ST trials, respectively, and to 198 (58.4%) in the DST. In multivariable-adjusted analyses, there was no association between cognitive performance and BL except for a weak but opposite association in DST; for a 10-fold BL increment, mean total latency was 5.4% (95% confidence interval, -0.4-11.5%; P=0.066) higher, whereas the error score was 42% (-10-69%; P=0.096) lower. To exclude an effect of the cumulative lead dose, sensitivity analyses restricted to workers

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 (NO2), particulate matter

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

Introduction: Four epidemiological studies have shown a negative association between prenatal acrylamide exposure and birth size. In order to shed light on the possible underlying mechanism(s), we analysed associations between acrylamide biomarkers and biomarkers related to fetal growth. Methods: In newborns of the ENVIRONAGE birth cohort (n ranges from 215 to 434), we investigated the association between prenatal acrylamide exposure (acrylamide and glycidamide hemoglobin adduct levels in cord blood) and thyroid hormones (TSH, T3, T4 and the ratio of T4 to T3 in cord plasma), insulin-related factors (cord plasma insulin and IGF1, and placental IGF2), neurotrophins (cord plasma BDNF, and placental NGF, NT3 and NT4), and cord plasma homocysteine and progesterone, using multiple linear regression analysis. In addition, we investigated whether the biomarkers mediated the associations between prenatal acrylamide exposure and birth outcomes. Results: We observed lower cord plasma TSH (-10.2% [95% CI: -15.0, -4.3]) and higher placental NGF levels (10.0% [95% CI 3.7, 17.4]) for a twofold increase of acrylamide adducts, a decrease in the ratio of cord plasma free T4 and free T3 with higher acrylamide and glycidamide adducts of -2.9% (95% CI: -5.7, -0.1) and -3.9% (95% CI: -6.2, -1.6) for a twofold increase in acrylamide and glycidamide adduct levels, respectively, and higher cord plasma free T3 with increases in both acrylamide and glycidamide adducts of 2.8% (95% CI: 0.2, 5.6) and 3.6% (95% CI: 0.8, 6.6) for a twofold increase in acrylamide and glycidamide adduct levels, respectively. Additionally, a twofold increase in glycidamide adducts was associated with lower cord plasma insulin levels, particularly among newborns of non-smoking mothers (-11.2% [95% CI: -19.5, -0.1]). Cord plasma insulin seemed to mediate the association between glycidamide adducts and birth weight. Conclusions: A decrease in cord plasma insulin levels may be (a marker of) a mechanism by which gestational acrylamide exposure is associated with decreased fetal growth. The possible health consequences of the associations between gestational acrylamide exposure and thyroid hormones and neurotrophins warrant future study. European Research CouncilEuropean Research Council (ERC)European Commission [ERC-2012-StG310898]; Research Foundation - Flanders (FWO)FWO [1516112N/G.0873.11.N.10, 12J9516N, 1524517N]

Background In environmental epidemiology, air pollution exposure is often estimated at the population level. To avoid the risk of exposure misclassification, one possibility is to interpolate air pollution measures at the residence through Geographical Information Systems. However, this might imply cumbersome administrative procedures. Data on air pollution annoyance from surveys can be an alternative to assess individual exposure to air pollution. This study investigates the association between air pollution annoyance and individual air pollution exposure. Methods Analyses were carried out based on a linkage of data from the Belgian Health Interview Survey (HIS 2008 and 2013; >15 years; n = 9347) and annual means of air pollution concentration at the residence. Self-reported air pollution annoyance was assessed through a five-point Likert scale. Statistical analyses included Spearman correlation coefficient, analysis of variance and multivariable ordinal logistic regressions (OLR). Results A significant exposure-response relationship was observed between long-term air pollution exposure and self-reported air pollution annoyance. However, Spearman coefficients were low (0.18-0.24), meaning a high heterogeneity of annoyance levels for a given exposure. In multivariable OLR, the odds of being annoyed by air pollution was 2.10 (95% CI: 1.86-2.67) times higher for each Interquartile range (IQR) increase in NO2 concentration (PM2.5: 1.77 [95% CI: 1.53-2.07], PM10: 1.61 [95% CI: 1.33-1.67], black carbon: 1.45 [95% CI: 1.27-1.67]). Air pollution annoyance depended largely on individual factors especially health status. Conclusions Air pollution exposure has a significant influence on self-reported air pollution annoyance. However, many other factors were found to influence annoyance, independently of the exposure. We found a limited validity of self-reported air pollution annoyance to assess individual long-term exposure to air pollution. Key messages Significant exposure-response relationship between individual long-term air pollution exposure and self-reported air pollution annoyance. Limited validity of self-reported air pollution annoyance for assessing individual long term exposure to air pollution.

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.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.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.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.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.

BACKGROUND: Exposure to particulate air pollution has been linked with risk of carcinogenesis. Damage to repair pathways might have long-term adverse health effects. We aimed to investigate the association of prenatal exposure to air pollution with placental mutation rate and the DNA methylation of key placental DNA repair genes. METHODS: This cohort study used data from the ongoing ENVironmental Influence ON early AGEing (ENVIRONAGE) birth cohort, which enrols pairs of mothers and neonates (singleton births only) at the East-Limburg Hospital (Genk, Belgium). Placental DNA samples were collected after birth. We used bisulfite-PCR-pyrosequencing to investigate the mutation rate of Alu (a marker for overall DNA mutation) and DNA methylation in the promoter genes of key DNA repair and tumour suppressor genes (APEX1, OGG1, PARP1, ERCC1, ERCC4, p53, and DAPK1). We used a high-resolution air pollution model to estimate exposure to particulate matter with a diameter less than 2·5 μm (PM2·5), black carbon, and NO2 over the entire pregnancy on the basis of maternal address. Alu mutation was analysed with a linear regression model, and methylation values of the selected genes were analysed in mixed-effects models. Effect estimates are presented as the relative percentage change in methylation for an ambient air pollution increment of one IQR (ie, the difference between the first and third quartiles of exposure in the entire cohort). FINDINGS: 500 biobanked placental DNA samples were randomly selected from 814 pairs of mothers and neonates who were recruited to the cohort between Feb 1, 2010, and Dec 31, 2014, of which 463 samples met the pyrosequencing quality control criteria. IQR exposure increments were 3·84 μg/m3 for PM2·5, 0·36 μg/m3 for black carbon, and 5·34 μg/m3 for NO2. Among these samples, increased Alu mutation rate was associated with greater exposure to PM2·5 (r=0·26, p

Rationale: Ambient air pollution, including black carbon, entails a serious public health risk because of its carcinogenic potential and as climate pollutant. To date, an internal exposure marker for black carbon particles that have cleared from the systemic circulation into the urine does not exist. Objectives: To develop and validate a novel method to measure black carbon particles in a label-free way in urine. Methods: We detected urinary carbon load in 289 children (aged 9–12 yr) using white-light generation under femtosecond pulsed laser illumination. Children’s residential black carbon concentrations were estimated based on a high-resolution spatial temporal interpolation method. Measurements and Main Results: We were able to detect urinary black carbon in all children, with an overall average (SD) of 98.2 × 105 (29.8 × 105) particles/ml. The urinary black carbon load was positively associated with medium-term to chronic (1 mo or more) residential black carbon exposure: +5.33 × 105 particles/ml higher carbon load (95% confidence interval, 1.56 × 105 to 9.10 × 105 particles/ml) for an interquartile range increment in annual residential black carbon exposure. Consistently, children who lived closer to a major road (≤160 m) had higher urinary black carbon load (6.93 × 105 particles/ml; 95% confidence interval, 0.77 × 105 to 13.1 × 105). Conclusions: Urinary black carbon mirrors the accumulation of medium-term to chronic exposure to combustion-related air pollution. This specific biomarker reflects internal systemic black carbon particles cleared from the circulation into the urine, allowing investigators to unravel the complexity of particulate-related health effects. Funded by the European Research Council (ERC-2012-StG 310898), the Interuniversity Attraction Poles Program (P7/05) initiated by the Belgian Science Policy Office, and the Flemish Scientific Research Foundation (G082113/11ZB115N/12R6315N/G073315N).

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 (PM2.5 and PM10) and nitrogen dioxide (NO2) 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 PM2.5 exposure during pregnancy averaged (SD) 13.7μg/m3 (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

Background: Thyroid hormones are critical for fetal development and growth. Whether prenatal exposure to fine particle air pollution (PM2.5) affects fetal thyroid function and what the impact is on birth weight in normal healthy pregnancies is not studied yet. Objectives: To study the impact of third trimester PM2.5 exposure on fetal and maternal thyroid hormones and their mediating role on birth weight. Methods: We measured the levels of free thyroid hormones (FT3, FT4) and thyroid stimulating hormone (TSH) in cord blood (n = 499) and maternal blood (n = 431) collected after delivery from mother-child pairs enrolled between February 2010 and June 2014 in the ENVIRONAGE birth cohort with catchment area in the province of Limburg, Belgium. Results: An interquartile range (IQR) increment (+8.2 µg/m3 ) in third trimester PM2.5 exposure was inversely associated with cord blood TSH levels (-11.6%; 95% CI: -21.8, -0.1) and the FT4/FT3 ratio (-62.7%; -91.6, -33.8). A 10th-90th percentile decrease in cord blood FT4 levels was associated with a 56 g decrease in mean birth weight (95% CI: -90, -23). Assuming causality, we estimated that cord blood FT4 mediated 21% (-19 g; 95%CI: -37, -1) of the estimated effect of an IQR increment in third trimester PM2.5 exposure on birth weight. Third trimester PM2.5 exposure was inversely but not significantly associated with maternal blood FT4 levels collected one day after delivery (-4.0%, 95% CI: -8.0, 0.2 for an IQR increment in third trimester PM2.5). Conclusions: In our study population of normal healthy pregnancies, third trimester exposure to PM2.5 air pollution was associated with differences in fetal thyroid hormone levels that may contribute to reduced birth weight. Additional research is needed to confirm our findings in other populations and to evaluate potential consequences later in life. The ENVIRONAGE birth cohort is supported by the European Research Council (ERC-2012-StG.310898), by the Flemish Scientific Fund (FWO, N1516112 / G.0.873.11.N.10) and the Bijzonder Onderzoeksfonds (BOF) of Hasselt University. Karen Vrijens is a postdoctoral fellow of the FWO.

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. This review is supported by grants from the European Research Council (ERC-2012-StG 310898/POC INCALO) and FWO (G082317 N).

The placenta plays a crucial role in fetal growth and development through adaptive responses to perturbations of the maternal environment. We investigated the association between placental 3-nitrotyrosine (3-NTp), a biomarker of oxidative stress, and exposure to air pollutants during various time windows of pregnancy. We measured placental 3-NTp of 330 mother-newborn pairs, enrolled in the ENVIRONAGE birth cohort (2010 to 2013). Daily particulate matter ≤ 2.5 µm (PM2.5), black carbon (BC), and nitrogen dioxide concentrations were interpolated for each mother’s residence using a spatiotemporal interpolation method. Placental 3-NTp levels, adjusted for covariates, increased by 35.0% (95% confidence interval (CI): 13.9, 60.0%) for an interquartile range increment in entire pregnancy PM2.5 exposure. The corresponding estimate for BC exposure was 13.9% (95% CI: -0.21, 29.9%). These results were driven by the first [PM2.5: 29.0% (95% CI: 4.9, 58.6%); BC: 23.6% (95% CI: 4.4, 46.4%)] and second gestational exposure window [PM2.5: 39.3% (95% CI: 12.3, 72.7)]. This link between placental nitrosative stress and exposure to fine particle air pollution during gestation is in line with experimental evidence on cigarette smoke and diesel exhaust exposure. Further research is needed to elucidate potential health consequences later in life through particle-mediated nitrosative stress during fetal life. This work was supported by the European Research Council (Grant ERC-2012-StG 310898) and by the Flemish Scientific Fund (Grants G.073315N, 1516112N and 12D7714N to K.V.).

Introduction Mental health issues appear as a growing problem in modern societies and tend to be more frequent in big cities. Where increased evidence exists for positive links between nature and mental health, associations between urban environment characteristics and mental health are still not well understood. These associations are highly complex and require an interdisciplinary and integrated research approach to cover the broad range of mitigating factors. This article presents the study protocol of a project called Nature Impact on Mental Health Distribution that aims to generate a comprehensive understanding of associations between mental health and the urban residential environment. Methods and analysis Following a mixed-method approach, this project combines quantitative and qualitative research. In the quantitative part, we analyse among the Brussels urban population associations between the urban residential environment and mental health, taking respondents' socioeconomic status and physical health into account. Mental health is determined by the mental health indicators in the national Health Interview Survey (HIS). The urban residential environment is described by subjective indicators for the participant's dwelling and neighbourhood present in the HIS and objective indicators for buildings, network infrastructure and green environment developed for the purpose of this project. We assess the mediating role of physical activity, social life, noise and air pollution. In the qualitative part, we conduct walking interviews with Brussels residents to record their subjective well-being in association with their neighbourhood. In the validation part, results from these two approaches are triangulated and evaluated through interviews and focus groups with stakeholders of healthcare and urban planning sectors. Ethics and dissemination The Privacy Commission of Belgium and ethical committee from University Hospital of Antwerp respectively approved quantitative database merging and qualitative interviewing. We will share project results with a wide audience including the scientific community, policy authorities and civil society through scientific and non-expert communication. This work was supported by the Belgian Federal Science Policy Office (BELSPO), grant number BR/175/A3/NAMED. Lauwers, L (corresponding author), Univ Antwerp, Dept Primary & Interdisciplinary Care, Fac Med & Hlth Sci, Antwerp, Belgium. laura.lauwers@uantwerpen.be

Epigenetic regulation is hereditable but can be influenced by environmental stimuli, in utero circumstances, and aging. Different layers of epigenetic remodeling including DNA methylation, modifications of histone tails, and noncoding RNAs control the spatial and temporal transcriptomic activity. In addition, the epigenome is involved in sustaining chromosome stability. Genomic DNA isolated from blood cells or other pertinent tissues is being expansively exploited for the discovery of biomarkers of effect and exposure. Technology to measure epigenetic marks on a genomic scale complemented with novel tools for data-analysis have recently been developed and continue to be enhanced. Here, we describe common techniques that are applied for untargeted approaches; and to measure regional modifications and gene-specific aberrations. Alterations in epigenetic marks have been associated with various exposures such as tobacco smoke, air pollution, and metal exposures in population-based studies. On the other hand, deviant DNA methylation is a major epigenetic mechanism of epigenetic silencing in a wide range of human diseases including cancers. Epigenetic modifications might play a prominent role in explaining biological mediation of exposures and their effect on health. This is of particular significance in early life exposures where epigenetic alterations can explain how diseases linked to in utero or childhood conditions occur later in life. We discuss relevant examples of how epigenetic remodeling by environmental stimuli affects several health outcomes in adults and in early life.

Background: Exposure to air pollution during pregnancy may increase several behavior problems, including depression/anxiety or conduct/aggressive problems in children, but findings have been incons...

The sustainability of cobalt is an important emerging issue because this critical base metal is an essential component of lithium-ion batteries for electric vehicles. More than half of the world’s cobalt mine production comes from the Katanga Copperbelt in DR Congo, with a substantial proportion (estimated at 15–20%) being extracted by artisanal miners. Here we show, in a case study performed in the town of Kolwezi, that people living in a neighbourhood that had been transformed into an artisanal cobalt mine had much higher levels of cobalt in their urine and blood than people living in a nearby control area. The differences were most pronounced for children, in whom we also found evidence of exposure-related oxidative DNA damage. It was already known that industrial mining and processing of metals has led to severe environmental pollution in the region. This field study provides novel and robust empirical evidence that the artisanal extraction of cobalt that prevails in the DR Congo may cause toxic harm to vulnerable communities. This strengthens the conclusion that the currently existing cobalt supply chain is not sustainable. Cobalt is used in rechargeable batteries, and half the world’s supply comes from one district in the Democratic Republic of Congo. This study assesses the sustainability of artisanal mining there, finding much higher levels of cobalt in blood and urine of community members and especially of children.

An imbalance between energy uptake and energy expenditure is the most important reason for increasing trends in obesity starting from early in life. Extracellular miRNAs are expressed in all bodily fluids and their expression is influenced by a broad range of stimuli. We examined whether screen time, physical activity and BMI are associated with children's salivary extracellular miR-222 and miR-146a expression. In 80 children the extracellular fraction of saliva was obtained by means of differential centrifugation and ultracentrifugation. Expression levels of miR-222 and miR-146a were profiled by qPCR. We studied the association between children's salivary extracellular miRNA expression and screen time, physical activity and BMI using mixed models, while accounting for potential confounders. We found that higher screen time was positively associated with salivary extracellular miR-222 and miR-146a levels. On average, one hour more screen time use per week was associated with a 3.44% higher miR-222 (95% CI: 1.34 to 5.58; p = 0.002) and 1.84% higher miR-146a (95% CI: -0.04 to 3.75; p = 0.055) level in saliva. BMI and physical activity of the child were not significantly associated with either miR-222 or miR-146a. A sedentary behaviour, represented by screen time use in children, is associated with discernible changes in salivary expression of miR-146a and or miR-222. These miRNA targets may emerge attractive candidates to explore the role of these exposures in developmental processes of children's health. The authors thank Michal Kicinski for his contributions during the COGNAC study. The COGNAC study is supported by grants from the European Research Council (ERC-2012-StG310898) and the Flemish Scientific Fund (FWO, 1516112 N/G.0873.11.N.10). AV has a PhD fellowship from Bijzonder Onderzoeksfonds (BOF) Hasselt University. KV has a postdoctoral fellowship of the Research Foundation - Flanders (FWO), 12D7718N. Datasets generated during the study can be obtained through the corresponding author upon reasonable request.

Introduction Particulate air pollution is probably causally related to increased risk of cardiovascular disease. Plasma homocysteine is an established cardiovascular disease risk factor. Recent studies show that exposure to particulate air pollution is associated with plasma homocysteine levels in adults but no studies on the association between prenatal air pollution and neonatal homocysteine levels exist. Methods In 609 newborns of the ENVIRONAGE (ENVIRonmental influence ON early AGEing) birth cohort, we investigated the association between prenatal particulate matter exposure with a diameter ≤ 2.5 µm (PM2.5) and cord plasma homocysteine levels, and in a subset (n = 490) we studied the interaction with 11 single nucleotide polymorphism (SNPs) in oxidative stress-related genes (CAT, COMT, GSTP1, SOD2, NQO1 and HFE), through multiple linear regression. PM2.5 levels were obtained using a high resolution spatial temporal interpolation method. Homocysteine levels were measured by the homocysteine enzymatic assay on a Roche/Hitachi cobas c system. SNPs were assessed on the Biotrove OpenArray SNP genotyping platform. Results In multivariable-adjusted models, cord plasma homocysteine levels were 8.1% higher (95% CI: 1.9 to 14.3%; p = 0.01) for each 5 µg/m³ increment in average PM2.5 exposure during the entire pregnancy. With regard to pregnancy trimesters, there was only an association in the 2nd trimester: 3.6% (95% CI: 0.9% to 6.4%; p = 0.01). The positive association between PM2.5 in and homocysteine was (borderline) statistically significantly modified by genetic variants in MnSOD (p interaction = 0.02), GSTP1 (p interaction = 0.07) and the sum score of the 3 studied SNPs in the CAT gene (p interaction=0.09), suggesting oxidative stress as an underlying mechanism of action. Conclusions Exposure to particulate air pollution in utero is associated with higher cord blood homocysteine levels, possibly through generating oxidative stress. Increased air pollution-induced homocysteine levels in early life might predispose for cardiovascular and other diseases later in life.

In mammals, a central clock maintains the daily rhythm in accordance with the external environment. At the molecular level, the circadian rhythm is maintained by epigenetic regulation of the Circadian pathway. Here, we tested the role of particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM2.5) exposure during gestational life on human placental Circadian pathway methylation, as an important molecular target for healthy development. In 407 newborns, we quantified placental methylation of CpG sites within the promoter regions of the following genes: CLOCK, BMAL1, NPAS2, CRY1-2 and PER1-3 using bisulfite-PCR-pyrosequencing. Daily PM2.5 exposure levels were estimated for each mother's residence, using a spatiotemporal interpolation model. We applied mixed-effects models to study the methylation status of the Circadian pathway genes and in utero PM2.5 exposure, while adjusting for a priori chosen covariates. In a multi-gene model, placental Circadian pathway methylation was positively and significantly (p

Background: Air pollution exposure during pregnancy has been associated with adverse birth outcomes and health problems later in life. We investigated sex-specific transcriptomic responses to gestational long-and short-term exposure to particulate matter with a diameter < 2.5 mu m ( PM2.5) in order to elucidate potential underlying mechanisms of action. Methods: Whole genome gene expression was investigated in cord blood of 142 mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. Daily PM2.5 exposure levels were calculated for each mother's home address using a spatial-temporal interpolation model in combination with a dispersion model to estimate both long- (annual average before delivery) and short- (last month of pregnancy) term exposure. We explored the association between gene expression levels and PM2.5 exposure, and identified modulated pathways by overrepresentation analysis and gene set enrichment analysis. Results: Some processes were altered in both sexes for long-(e.g. DNA damage) or short-term exposure (e.g. olfactory signaling). For long-term exposure in boys neurodevelopment and RhoA pathways were modulated, while in girls defensin expression was down-regulated. For short-term exposure we identified pathways related to synaptic transmission and mitochondrial function (boys) and immune response (girls). Conclusions: This is the first whole genome gene expression study in cord blood to identify sex-specific pathways altered by PM2.5. The identified transcriptome pathways could provide new molecular insights as to the interaction pattern of early life PM2.5 exposure with the biological development of the fetus. This research is funded by the European Research Council (ERC-2012-stG310898) and the Flemish Scientific Fund (FWO, G073315N). Ellen Winckelmans has a PhD. fellowship of Hasselt University (BOF program).

Background: Particulate matter with a diameter ≤ 2.5 μm (PM2.5) affects human fetal development during pregnancy. Oxidative stress is a putative mechanism by which PM2.5 may exert its effects. Leptin (LEP) is an energy-regulating hormone involved in fetal growth and development. Objectives: We investigated in placental tissue whether DNA methylation of the LEP promoter is associated with PM2.5 and whether the oxidative/nitrosative stress biomarker 3-nitrotyrosine (3-NTp) is involved. Methods: LEP DNA methylation status of 361 placentas from the ENVIRONAGE birth cohort was assessed using bisulfite-PCR-pyrosequencing. Placental 3-NTp (n = 313) was determined with an ELISA assay. Daily PM2.5 exposure levels were estimated for each mother’s residence, accounting for residential mobility during pregnancy, using a spatiotemporal interpolation model. Results: After adjustment for a priori chosen covariates, placental LEP methylation was 1.4% lower (95% CI: –2.7, –0.19%) in association with an interquartile range increment (7.5 μg/m3) in second-trimester PM2.5 exposure and 0.43% lower (95% CI: –0.85, –0.02%) in association with a doubling of placental 3-NTp content. Conclusions: LEP methylation status in the placenta was negatively associated with PM2.5 exposure during the second trimester, and with placental 3-NTp, a marker of oxidative/nitrosative stress. Additional research is needed to confirm our findings and to assess whether oxidative/nitrosative stress might contribute to associations between PM2.5 and placental epigenetic events. Potential consequences for health during the neonatal period and later in life warrant further exploration. Citation: Saenen ND, Vrijens K, Janssen BG, Roels HA, Neven KY, Vanden Berghe W, Gyselaers W, Vanpoucke C, Lefebvre W, De Boever P, Nawrot TS. 2017. Lower placental leptin promoter methylation in association with fine particulate matter air pollution during pregnancy and placental nitrosative stress at birth in the ENVIRONAGE cohort. Environ Health Perspect 125:262–268; http://dx.doi.org/10.1289/EHP38

Background: Microvascular changes may represent an underlying mechanism through which exposure to fine particulate matter with a diameter ≤ 2.5 μm (PM2.5) contributes to age-related disease development. We investigated the effect of recent and chronic exposure to PM2.5 on the microcirculation, exemplified by retinal vessel diameters, using repeated measurements in 8- to 12-year-old children. Methods: 221 children (49.1% girls; mean age 9.9 years) were examined repeatedly (25 one, 124 two, and 72 three times) adding up to 489 retinal vessel examinations. Same-day exposure to PM2.5 was measured at school. In addition, recent (same and previous day) and chronic (yearly mean) exposure was modelled at the child's residence using a high-resolution interpolation model. Residential proximity to major roads was also assessed. Changes in retinal vessel diameters associated with recent and chronic exposures were estimated using mixed models, while adjusting for other known covariates such as sex, age, BMI, blood pressure and birth weight. Results: Each 10 μg/m³ increment in same-day exposure to PM2.5 measured at school was associated with 0.35 μm (95% CI: 0.09–0.61 μm) narrower retinal arterioles and 0.35 μm (−0.03 to 0.73 μm) wider venules. Children living 100 m closer to a major road had 0.30 μm (0.05–0.54 μm) narrower arterioles. Conclusions: Blood vessel diameters of the retinal microcirculation of healthy school-aged children respond to same-day PM2.5 exposure. Furthermore, children living closer to major roads had smaller arteriolar diameters. Our results suggest that the microcirculation, with retinal microvasculature as a proxy in this study, is a pathophysiological target for air pollution in children. This work was supported by the EU Program "Ideas" [ERC-2012-StG 310898] and Research Foundation - Flanders (FWO) [G073315N]; E.B.P. has a VITO-FWO Ph.D. fellowship and K.V. holds an FWO Postdoc scholarship.