Placental DNA methylation signatures of prenatal air pollution exposure and potential effects on birth outcomes: an analysis of three prospective cohorts.

BACKGROUND: Pregnancy air pollution exposure (PAPE) has been linked to a wide range of adverse birth and childhood outcomes, but there is a paucity of data on its influence on the placental epigenome, which can regulate the programming of physiological functions and affect child development. This study aimed to investigate the association between prenatal air pollutant exposure concentrations and changes in placental DNA methylation patterns, and to explore the potential windows of susceptibility and sex-specific alterations. METHODS: This multi-site study used three prospective population-based mother-child cohorts: EDEN, PELAGIE, and SEPAGES, originating from four French geographical regions (Nancy, Poitiers, Brittany, and Grenoble). Pregnant women were included between 2003 and 2006 for EDEN and PELAGIE, and between 2014 and 2017 for SEPAGES. The main eligibility criteria were: being older than 18 years, having a singleton pregnancy, and living and planning to deliver in one of the maternity clinics in one of the study areas. A total of 1539 mother-child pairs were analysed, measuring placental DNA methylation using Illumina BeadChips. We used validated spatiotemporally resolved models to estimate PM2·5, PM10, and NO2 exposure over each trimester of pregnancy at the maternal residential address. We conducted a pooled adjusted epigenome-wide association study to identify differentially methylated 5'-C-phosphate-G-3' (CpG) sites and regions (assessed using the Infinium HumanMethylationEPIC BeadChip array, n=871), including sex-specific and sex-linked alterations, and independently validated our results (assessed using the Infinium HumanMethylation450 BeadChip array, n=668). FINDINGS: We identified four CpGs and 28 regions associated with PAPE in the total population, 469 CpGs and 87 regions in male infants, and 150 CpGs and 66 regions in female infants. We validated 35% of the CpGs available. More than 30% of the identified CpGs were related to one (or more) birth outcome and most significant alterations were enriched for neural development, immunity, and metabolism related genes. The 28 regions identified for both sexes overlapped with imprinted genes (four genes), and were associated with neurodevelopment (nine genes), immune system (seven genes), and metabolism (five genes). Most associations were observed for the third trimester for female infants (134 of 150 CpGs), and throughout pregnancy (281 of 469 CpGs) and the first trimester (237 of 469 CpGs) for male infants. INTERPRETATION: These findings highlight the molecular pathways through which PAPE might affect child health in a widespread and sex-specific manner, identifying the genes involved in the major physiological functions of a developing child. Further studies are needed to elucidate whether these epigenetic changes persist and affect health later in life. FUNDING: French Agency for National Research, Fondation pour la Recherche Médicale, Fondation de France, and the Plan Cancer.

Prenatal and childhood exposure to ambient air pollution and cognitive function in school-age children: Examining sensitive windows and sex-specific associations.

BACKGROUND: Combined effect of both prenatal and early postnatal exposure to ambient air pollution on child cognition has rarely been investigated and periods of sensitivity are unknown. This study explores the temporal relationship between pre- and postnatal exposure to PM10, PM2.5, NO2 and child cognitive function. METHODS: Using validated spatiotemporally resolved exposure models, pre- and postnatal daily PM2.5, PM10 (satellite based, 1 km resolution) and NO2 (chemistry-transport model, 4 km resolution) concentrations at the mother's residence were estimated for 1271 mother-child pairs from the French EDEN and PELAGIE cohorts. Scores representative of children's General, Verbal and Non-Verbal abilities at 5-6 years were constructed based on subscale scores from the WPPSI-III, WISC-IV or NEPSY-II batteries, using confirmatory factor analysis (CFA). Associations of both prenatal (first 35 gestational weeks) and postnatal (60 months after birth) exposure to air pollutants with child cognition were explored using Distributed Lag Non-linear Models adjusted for confounders. RESULTS: Increased maternal exposure to PM10, PM2.5 and NO2, during sensitive windows comprised between the 15th and the 33rd gestational weeks, was associated with lower males' General and Non-verbal abilities. Higher postnatal exposure to PM2.5 between the 35th and 52nd month of life was associated with lower males' General, Verbal and Non-verbal abilities. Some protective associations were punctually observed for the very first gestational weeks or months of life for both males and females and the different pollutants and cognitive scores. DISCUSSION: These results suggest poorer cognitive function at 5-6 years among males following increased maternal exposure to PM10, PM2.5 and NO2 during mid-pregnancy and child exposure to PM2.5 around 3-4 years. Apparent protective associations observed are unlikely to be causal and might be due to live birth selection bias, chance finding or residual confounding.

Association of Prenatal and Postnatal Exposures to Warm or Cold Air Temperatures With Lung Function in Young Infants.

Importance: Little is known about long-term associations of early-life exposure to extreme temperatures with child health and lung function. Objectives: To investigate the association of prenatal and postnatal heat or cold exposure with newborn lung function and identify windows of susceptibility. Design, Setting, and Participants: This population-based cohort study (SEPAGES) recruited pregnant women in France between July 8, 2014, and July 24, 2017. Data on temperature exposure, lung function, and covariates were available from 343 mother-child dyads. Data analysis was performed from January 1, 2021, to December 31, 2021. Exposures: Mean, SD, minimum, and maximum temperatures at the mother-child's residence, estimated using a state-of-the-art spatiotemporally resolved model. Main Outcomes and Measures: Outcome measures were tidal breathing analysis and nitrogen multiple-breath washout test measured at 2 months of age. Adjusted associations between both long-term (35 gestational weeks and first 4 weeks after delivery) and short-term (7 days before lung function test) exposure to ambient temperature and newborn lung function were analyzed using distributed lag nonlinear models. Results: A total of 343 mother-child pairs were included in the analyses (median [IQR] maternal age at conception, 32 [30.0-35.2] years; 183 [53%] male newborns). A total of 246 mothers and/or fathers (72%) held at least a master's degree. Among the 160 female newborns (47%), long-term heat exposure (95th vs 50th percentile of mean temperature) was associated with decreased functional residual capacity (-39.7 mL; 95% CI, -68.6 to -10.7 mL for 24 °C vs 12 °C at gestational weeks 20-35 and weeks 0-4 after delivery) and increased respiratory rate (28.0/min; 95% CI, 4.2-51.9/min for 24 °C vs 12 °C at gestational weeks 14-35 and weeks 0-1 after delivery). Long-term cold exposure (5th vs 50th percentile of mean temperature) was associated with lower functional residual capacity (-21.9 mL; 95% CI, -42.4 to -1.3 mL for 1 °C vs 12 °C at gestational weeks 15-29), lower tidal volume (-23.8 mL; 95% CI, -43.1 to -4.4 mL for 1 °C vs 12 °C at gestational weeks 14-35 and weeks 0-4 after delivery), and increased respiratory rate (45.5/min; 95% CI, 10.1-81.0/min for 1 °C vs 12 °C at gestational weeks 6-35 and weeks 0-1 after delivery) in female newborns as well. No consistent association was observed for male newborns or short-term exposure to cold or heat. Conclusions and Relevance: In this cohort study, long-term heat and cold exposure from the second trimester until 4 weeks after birth was associated with newborn lung volumes, especially among female newborns.

Early delivery following chronic and acute ambient temperature exposure: a comprehensive survival approach.

BACKGROUND: Ambient temperature, particularly heat, is increasingly acknowledged as a trigger for preterm delivery but study designs have been limited and results mixed. We aimed to comprehensively evaluate the association between ambient temperature throughout pregnancy and preterm delivery. METHODS: We estimated daily temperature throughout pregnancy using a cutting-edge spatiotemporal model for 5347 live singleton births from three prospective cohorts in France, 2002-2018. We performed Cox regression (survival analysis) with distributed lags to evaluate time-varying associations with preterm birth simultaneously controlling for exposure during the first 26 weeks and last 30 days of pregnancy. We examined weekly mean, daytime, night-time and variability of temperature, and heatwaves accounting for adaptation to location and season. RESULTS: Preterm birth risk was higher following cold (5th vs 50th percentile of mean temperature) 7-9 weeks after conception [relative risk (RR): 1.3, 95% CI: 1.0-1.6 for 2°C vs 11.6°C] and 10-4 days before delivery (RR: 1.6, 95% CI: 1.1-2.1 for 1.2°C vs 12.1°C). Night-time heat (95th vs 50th percentile of minimum temperature; 15.7°C vs 7.4°C) increased risk when exposure occurred within 5 weeks of conception (RR: 2.0, 95% CI: 1.05-3.8) or 20-26 weeks after conception (RR: 2.9, 95% CI: 1.2-6.8). Overall and daytime heat (high mean and maximum temperature) showed consistent effects. We found no clear associations with temperature variability or heatwave indicators, suggesting they may be less relevant for preterm birth. CONCLUSIONS: In a temperate climate, night-time heat and chronic and acute cold exposures were associated with increased risk of preterm birth. These results suggest night-time heat as a relevant indicator. In the context of rising temperatures and more frequent weather hazards, these results should inform public health policies to reduce the growing burden of preterm births.

Associations between a mixture of phenols and phthalates and child behaviour in a French mother-child cohort with repeated assessment of exposure.

BACKGROUND: Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects. OBJECTIVES: To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements. METHODS: We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median = 21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother-child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5-5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions). RESULTS: The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95 %CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95 %CI: -0.42, 3.81) and 1.17 points (95 %CI: -0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score. DISCUSSION: Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds.

Urban environment and mental health: the NAMED project, protocol for a mixed-method study.

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.

Personal exposure to traffic-related air pollutants and relationships with respiratory symptoms and oxidative stress: A pilot cross-sectional study among urban green space workers.

Exposure to ambient air pollution has been associated with various adverse health effects including respiratory, cardiovascular and neurological diseases. Exposure data for some specific pollutants and settings are however still insufficient and mechanisms underlying negative health outcomes are not fully elucidated. This pilot study aimed to assess individual exposure to three traffic-related air pollutants, black carbon (BC), polycyclic aromatic hydrocarbons (PAHs) and benzene, and the relationship with respiratory and oxidative stress outcomes in a cross-sectional sample of 48 green space workers in Brussels, Belgium. Participants were followed during four consecutive working days in 2016-2017 during which their individual exposure to BC, PAHs, benzene and more generally air pollution was measured using aethalometers, urinary biomarkers (1-hydroxypyrene, 1-naphthol, 2-naphthol, S-phenylmercapturic acid) and questionnaires. Data on respiratory health and oxidative stress were collected using questionnaires and respiratory/urinary biomarkers (exhaled nitric oxide [NO], 8-hydroxydeoxyguanosine [8-OHdG]). Associations between exposure and health outcomes were investigated using comparison tests and linear regression models, after stratification by present-day smoking status. Spatial variation in BC exposure was high, with concentrations varying between 0.26 and 5.69 µg/m3. The highest levels were recorded during transport and, to a lesser extent, in green spaces located in the vicinity of roads with high traffic intensity. Concentrations of PAHs and benzene biomarkers did not systematically exceed the limits of detection. Among smokers, respiratory inflammation increased linearly with exposure to BC measured over the four days of follow-up (ß = 8.73, 95% CI: 4.04, 13.41). Among non-smokers, oxidative stress increased linearly with BC measured on the fourth day (ß = 2.88, 95% CI: 1.52, 4.24). Despite some limitations, this work supports the hypothesis that BC induces respiratory inflammation and oxidative stress. It also highlights the value of this compound as well as exhaled NO and urinary 8-OHdG biomarkers to detect early/mild effects of air pollution.

Relationships between aeroallergen levels and hospital admissions for asthma in the Brussels-Capital Region: a daily time series analysis.

BACKGROUND: Outdoor pollen grain and fungal spore concentrations have been associated with severe asthma exacerbations at the population level. The specific impact of each taxon and the concomitant effect of air pollution on these symptoms have, however, still to be better characterized. This study aimed to investigate the short-term associations between ambient concentrations of various aeroallergens and hospitalizations related to asthma in the Brussels-Capital Region (Belgium), an area recording especially high rates of admissions. METHODS: Based on administrative records of asthma hospitalizations and regular monitoring of 11 tree/herbaceous pollen taxa and 2 fungal spore taxa, daily time series analyses covering the 2008-2013 period were performed. Effects up to 6 days after exposure were captured by combining quasi-Poisson regression with distributed lag models, adjusting for seasonal and long-term trends, day of the week, public holidays, mean temperature and relative humidity. Effect modification by age and air pollution (PM, NO2, O3) was tested. RESULTS: A significant increase in asthma hospitalizations was observed for an interquartile range increase in grass (5.9%, 95% CI: 0.0, 12.0), birch (3.2%, 95% CI: 1.1, 5.3) and hornbeam (0.7%, 95% CI: 0.2, 1.3) pollen concentrations. For several taxa including grasses, an age modification effect was notable, the hospitalization risk tending to be higher in individuals younger than 60 years. Air pollutants impacted the relationships too: the risk appeared to be stronger for grass and birch pollen concentrations in case of high PM10 and O3 concentrations respectively. CONCLUSIONS: These findings suggest that airborne grass, birch and hornbeam pollen are associated with severe asthma exacerbations in the Brussels region. These compounds appear to act in synergy with air pollution and to more specifically affect young and intermediate age groups. Most of these life-threatening events could theoretically be prevented with improved disease diagnosis/management and targeted communication actions.

Short-Term Effect of Pollen and Spore Exposure on Allergy Morbidity in the Brussels-Capital Region.

Belgium is among the European countries that are the most affected by allergic rhinitis. Pollen grains and fungal spores represent important triggers of symptoms. However, few studies have investigated their real link with disease morbidity over several years. Based on aeroallergen counts and health insurance datasets, the relationship between daily changes in pollen, fungal spore concentrations and daily changes in reimbursable systemic antihistamine sales has been investigated between 2005 and 2011 in the Brussels-Capital Region. A Generalized Linear Model was used and adjusted for air pollution, meteorological conditions, flu, seasonal component and day of the week. We observed an augmentation in drug sales despite no significant increase in allergen levels in the long term. The relative risk of buying allergy medications associated with an interquartile augmentation in pollen distributions increased significantly for Poaceae, Betula, Carpinus, Fraxinus and Quercus. Poaceae affected the widest age group and led to the highest increase of risk which reached 1.13 (95% CI [1.11-1.14]) among the 19- to 39-year-old men. Betula showed the second most consistent relationship across age groups. Clear identification of the provoking agents may improve disease management by customizing prevention programmes. This work also opens several research perspectives related to impact of climate modification or subpopulation sensitivity.

Oxidative stress pathways involved in cytotoxicity and genotoxicity of titanium dioxide (TiO2) nanoparticles on cells constitutive of alveolo-capillary barrier in vitro.

The health risks of nanoparticles remain a serious concern given their prevalence from industrial and domestic use. The primary route of titanium dioxide nanoparticle exposure is inhalation. The extent to which nanoparticles contribute to cellular toxicity is known to associate induction of oxidative stress. To investigate this problem further, the effect of titanium dioxide nanoparticles was examined on cell lines representative of alveolo-capillary barrier. The present study showed that all nanoparticle-exposed cell lines displayed ROS generation. Macrophage-like THP-1 and HPMEC-ST1.6R microvascular cells were sensitive to endogenous redox changes and underwent apoptosis, but not alveolar epithelial A549 cells. Genotoxic potential of titanium dioxide nanoparticles was investigated using the activation of γH2AX, activation of DNA repair proteins and cell cycle arrest. In the sensitive cell lines, DNA damage was persistent and activation of DNA repair pathways was observed. Moreover, western blot analysis showed that specific pathways associated with cellular stress response were activated concomitantly with DNA repair or apoptosis. Nanoparticles-induced oxidative stress is finally signal transducer for further physiological effects including genotoxicity and cytotoxicity. Within activated pathways, HSP27 and SAPK/JNK proteins appeared as potential biomarkers of intracellular stress and of sensitivity to endogenous redox changes, respectively, enabling to predict cell behavior.