Telomeres are nucleoprotein structures that cap the end of chromosomes. They can consist of several thousands of tandem-repeated TTAGGG sequences.^1,2 With each cellular division, telomeres shorten. Telomere length (TL) has been associated with age-related diseases and mortality and is considered a marker of biological aging.^3-8 Telomere length is also associated with environmental and lifestyle factors that influence the oxidative stress and inflammatory status in humans, such as smoking,⁹ obesity,¹⁰ Mediterranean diet,¹¹ exposure to violence,¹² and life stress,¹³ which underscores the vulnerability of telomeres to reactive oxygen species (ROS). In a 2015 update of the Global Burden of Disease study, ambient particulate matter (PM) was ranked as the sixth most leading risk factor influencing public health worldwide.¹⁴ Increased oxidative stress and inflammation are proposed as underlying mechanisms through which PM may influence human health.^15,16 Exposure to air pollution during in utero life may have adverse effects on the fetus and neonate.^17-19 The ability of PM air pollution to generate ROS has led to the hypothesis that telomere attrition is influenced by air pollution exposure.²⁰ Occupational and population-based studies have described both positive and negative associations between different types of air pollution and TL in adults.^21-27 In general, long-term exposure to PM²⁵ and black carbon (BC)^24,26 are associated with shorter TL in adults. Because TL is highly variable at birth,^28,29 potential determinants, such as newborn sex,²⁸ paternal age,²⁸ maternal prepregnancy body mass index (BMI),²⁰ maternal stress,³⁰ maternal educational level,³¹ maternal smoking during pregnancy,³² and maternal residential proximity to a major road,³³ have recently been explored for explaining this phenomenon. In this regard, we hypothesized that exposure to PM air pollution during pregnancy may contribute to telomere setting at birth. Because in utero life is believed to be a critical time window in the early programming of diseases later in life,³⁴ unravelling the connection between prenatal air pollution exposure and TL at birth may help to gain new insights in the causes of diseases linked with telomere biological characteristics. In this study, we assessed the association between prenatal exposure to PM_2.5 (particulate matter with an aerodynamic diameter ≤2.5 μm) and TL at birth.

Most research to date has focused on epigenetic modifications in the nuclear genome, with little attention devoted to mitochondrial DNA (mtDNA). Placental mtDNA content has been shown to respond to environmental exposures that induce oxidative stress, including airborne particulate matter (PM). Damaged or non-functioning mitochondria are specifically degraded through mitophagy, exemplified by lower mtDNA content, and could be primed by epigenetic modifications in the mtDNA. We studied placental mtDNA methylation in the context of the early life exposome. We investigated placental tissue from 381 mother-newborn pairs that were enrolled in the ENVIRONAGE birth cohort. We determined mtDNA methylation by bisulfite-pyrosequencing in 2 regions, i.e., the D-loop control region and 12S rRNA (MT-RNR1), and measured mtDNA content by qPCR. PM_2.5 exposure was calculated for each participant's home address using a dispersion model. An interquartile range (IQR) increment in PM_2.5 exposure over the entire pregnancy was positively associated with mtDNA methylation (MT-RNR1: +0.91%, P = 0.01 and D-loop: +0.21%, P = 0.05) and inversely associated with mtDNA content (relative change of −15.60%, P = 0.001) in placental tissue. mtDNA methylation was estimated to mediate 54% [P = 0.01 (MT-RNR1)] and 27% [P = 0.06 (D-loop)] of the inverse association between PM_2.5 exposure and mtDNA content. This study provides new insight into the mechanisms of altered mitochondrial function in the early life environment. Epigenetic modifications in the mitochondrial genome, especially in the MT-RNR1 region, substantially mediate the association between PM_2.5 exposure during gestation and placental mtDNA content, which could reflect signs of mitophagy and mitochondrial death.

Epidemiological studies suggest that residing close to green space reduce mortality rates. We investigated the relationship between long-term exposure to residential green space and non-accidental and cardio-respiratory mortality. We linked the Belgian 2001 census to population and mortality register follow-up data (2001-2011) among adults aged 30 years and older residing in the five largest urban areas in Belgium (n = 2,185,170 and mean follow-up time 9.4 years). Residential addresses were available at baseline. Exposure to green space was defined as 1) surrounding greenness (2006) [normalized difference vegetation index (NDVI) and modified soil-adjusted vegetation index (MSAVI2)] within buffers of 300 m, 500 m, and 1000 m; 2) surrounding green space (2006) [Urban Atlas (UA) and CORINE Land Cover (CLC)] within buffers of 300 m, 500 m, and 1000 m; and 3) perceived neighborhood green space (2001). Cox proportional hazards models with age as the underlying time scale were used to probe into cause-specific mortality (non-accidental, respiratory, COPD, cardiovascular, ischemic heart disease (IHD), and cerebrovascular). Models were adjusted for several sociodemographic variables (age, sex, marital status, country of birth, education level, employment status, and area mean income). We further adjusted our main models for annual mean (2010) values of ambient air pollution (PM2.5, PM10, NO2 and BC, one at a time), and we additionally explored potential mediation with the aforementioned pollutants. Higher degrees of residential green space were associated with lower rates of non-accidental and respiratory mortality. In fully adjusted models, hazard ratios (HR) per interquartile range (IQR) increase in NDVI 500 m buffer (IQR: 0.24) and UA 500 m buffer (IQR: 0.31) were 0.97 (95%CI 0.96-0.98) and 0.99 (95%CI 0.98-0.99) for non-accidental mortality, and 0.95 (95%CI 0.93-0.98) and 0.97 (95%CI 0.96-0.99) for respiratory mortality. For perceived neighborhood green space, HRs were 0.93 (95%CI 0.92-0.94) and 0.94 (95%CI 0.91-0.98) for non-accidental and respiratory mortality, respectively. The observed lower mortality risks associated with residential exposure to green space were largely independent from exposure to ambient air pollutants. We observed evidence for lower mortality risk in associations with long-term residential exposure to green space in most but not all studied causes of death in a large representative cohort for the five largest urban areas in Belgium. These findings support the importance of the availability of residential green space in urban areas.

Background: Thyroid hormones are critical for fetal development and growth. Whether prenatal exposure to fine particle air pollution (≤ 2.5 μm; PM2.5) affects fetal thyroid function and what the impact is on birth weight in normal healthy pregnancies have not been studied yet. Objectives: We studied 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%; 95% CI: –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 1 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. Citation: Janssen BG, Saenen ND, Roels HA, Madhloum N, Gyselaers W, Lefebvre W, Penders J, Vanpoucke C, Vrijens K, Nawrot TS. 2017. Fetal thyroid function, birth weight, and in utero exposure to fine particle air pollution: a birth cohort study. Environ Health Perspect 125:699–705; http://dx.doi.org/10.1289/EHP508

Background: Mitochondria are sensitive to environmental toxicants due to their lack of repair capacity. Changes in mitochondrial DNA (mtDNA) content may represent a biologically relevant intermediate outcome in mechanisms linking air pollution and fetal growth restriction. Objective: We investigated whether placental mtDNA content is a possible mediator of the association between prenatal nitrogen dioxide (NO2) exposure and birth weight. Methods: We used data from two independent European cohorts: INMA (n = 376; Spain) and ENVIRONAGE (n = 550; Belgium). Relative placental mtDNA content was determined as the ratio of two mitochondrial genes (MT-ND1 and MTF3212/R3319) to two control genes (RPLP0 and ACTB). Effect estimates for individual cohorts and the pooled data set were calculated using multiple linear regression and mixed models. We also performed a mediation analysis. Results: Pooled estimates indicated that a 10-μg/m3 increment in average NO2 exposure during pregnancy was associated with a 4.9% decrease in placental mtDNA content (95% CI: –9.3, –0.3%) and a 48-g decrease (95% CI: –87, –9 g) in birth weight. However, the association with birth weight was significant for INMA (–66 g; 95% CI: –111, –23 g) but not for ENVIRONAGE (–20 g; 95% CI: –101, 62 g). Placental mtDNA content was associated with significantly higher mean birth weight (pooled analysis, interquartile range increase: 140 g; 95% CI: 43, 237 g). Mediation analysis estimates, which were derived for the INMA cohort only, suggested that 10% (95% CI: 6.6, 13.0 g) of the association between prenatal NO2 and birth weight was mediated by changes in placental mtDNA content. Conclusion: Our results suggest that mtDNA content can be one of the potential mediators of the association between prenatal air pollution exposure and birth weight. Citation: Clemente DB, Casas M, Vilahur N, Begiristain H, Bustamante M, Carsin AE, Fernández MF, Fierens F, Gyselaers W, Iñiguez C, Janssen BG, Lefebvre W, Llop S, Olea N, Pedersen M, Pieters N, Santa Marina L, Souto A, Tardón A, Vanpoucke C, Vrijheid M, Sunyer J, Nawrot TS. 2016. Prenatal ambient air pollution, placental mitochondrial DNA content, and birth weight in the INMA (Spain) and ENVIRONAGE (Belgium) birth cohorts. Environ Health Perspect 124:659–665; http://dx.doi.org/10.1289/ehp.1408981