Dries S. Martens

Prenatal Air Pollution and Newborns' Predisposition to Accelerated Biological Aging

Importance Telomere length is a marker of biological aging that may provide a cellular memory of exposures to oxidative stress and inflammation. Telomere length at birth has been related to life expectancy. An association between prenatal air pollution exposure and telomere length at birth could provide new insights in the environmental influence on molecular longevity. Objective To assess the association of prenatal exposure to particulate matter (PM) with newborn telomere length as reflected by cord blood and placental telomere length. Design, Setting, and Participants In a prospective birth cohort (ENVIRONAGE [Environmental Influence on Ageing in Early Life]), a total of 730 mother-newborn pairs were recruited in Flanders, Belgium between February 2010 and December 2014, all with a singleton full-term birth (≥37 weeks of gestation). For statistical analysis, participants with full data on both cord blood and placental telomere lengths were included, resulting in a final study sample size of 641. Exposures Maternal residential PM2.5 (particles with an aerodynamic diameter ⩽2.5 &mgr;m) exposure during pregnancy. Main Outcomes and Measures In the newborns, cord blood and placental tissue relative telomere length were measured. Maternal residential PM2.5 exposure during pregnancy was estimated using a high-resolution spatial-temporal interpolation method. In distributed lag models, both cord blood and placental telomere length were associated with average weekly exposures to PM2.5 during pregnancy, allowing the identification of critical sensitive exposure windows. Results In 641 newborns, cord blood and placental telomere length were significantly and inversely associated with PM2.5 exposure during midgestation (weeks 12-25 for cord blood and weeks 15-27 for placenta). A 5-µg/m3 increment in PM2.5 exposure during the entire pregnancy was associated with 8.8% (95% CI, −14.1% to −3.1%) shorter cord blood leukocyte telomeres and 13.2% (95% CI, −19.3% to −6.7%) shorter placental telomere length. These associations were controlled for date of delivery, gestational age, maternal body mass index, maternal age, paternal age, newborn sex, newborn ethnicity, season of delivery, parity, maternal smoking status, maternal educational level, pregnancy complications, and ambient temperature. Conclusions and Relevance Mothers who were exposed to higher levels of PM2.5 gave birth to newborns with shorter telomere length. The observed telomere loss in newborns by prenatal air pollution exposure indicates less buffer for postnatal influences of factors decreasing telomere length during life. Therefore, improvements in air quality may promote molecular longevity from birth onward.

Air Pollution Stress and the Aging Phenotype: The Telomere Connection

Aging is a complex physiological phenomenon. The question why some subjects grow old while remaining free from disease whereas others prematurely die remains largely unanswered. We focus here on the role of air pollution in biological aging. Hallmarks of aging can be grouped into three main categories: genomic instability, telomere attrition, and epigenetic alterations leading to altered mitochondrial function and cellular senescence. At birth, the initial telomere length of a person is largely determined by environmental factors. Telomere length shortens with each cell division and exposure to air pollution as well as low residential greens space exposure is associated with shorter telomere length. Recent studies show that the estimated effects of particulate air pollution exposure on the telomere mitochondrial axis of aging may play an important role in chronic health effects of air pollution. The exposome encompasses all exposures over an entire life. As telomeres can be considered as the cellular memories of exposure to oxidative stress and inflammation, telomere maintenance may be a proxy for assessing the “exposome”. If telomeres are causally related to the aging phenotype and environmental air pollution is an important determinant of telomere length, this might provide new avenues for future preventive strategies.

Cohort Profile: The ENVIRonmental influence ON early AGEing (ENVIRONAGE): a birth cohort study

The ENVIRONAGE birth cohort is supported by the European Research Council [ERC-2012-StG.310898], and by funds of the Flemish Scientific Research council [FWO, G.0.733.15.N]. Bianca Cox, Janneke Hogervorst and Karen Vrijens have a postdoctoral fellowship from the Research Foundation - Flanders (FWO).

Neonatal Cord Blood Oxylipins and Exposure to Particulate Matter in the Early-Life Environment: An ENVIRONAGE Birth Cohort Study

Background: As part of the lipidome, oxylipins are bioactive lipid compounds originating from oxidation of different fatty acids. Oxylipins could provide a new target in the developmental origins model or the ability of early life exposure to change biology. Objectives: We studied the association between in utero PM2.5 (particulate matter with aerodynamic diameter < 2.5 μm) exposure and oxylipin profiles in newborns. Methods: Thirty-seven oxylipins reflecting the cyclooxygenase (COX), lipoxygenase (5-LOX and 12/15-LOX), and cytochrome P450 (CYP) pathways were assayed in 197 cord blood plasma samples from the ENVIRONAGE birth cohort. Principal component (PC) analysis and multiple regression models were used to estimate associations of in utero PM2.5 exposure with oxylipin pathways and individual metabolites. Results: A principal component representing the 5-LOX pathway (6 metabolites) was significantly positively associated with PM2.5 exposure during the entire (multiple testing–adjusted q-value = 0.05) and second trimester of pregnancy (q = 0.05). A principal component representing the 12/15-LOX pathway (11 metabolites) was positively associated with PM2.5 exposure during the second trimester of pregnancy (q = 0.05). PM2.5 was not significantly associated with the COX pathway during any time period. There was a positive but nonsignificant association between second-trimester PM2.5 and the CYP pathway (q = 0.16). Conclusion: In utero exposure to particulate matter, particularly during the second trimester, was associated with differences in the cord blood levels of metabolites derived from the lipoxygenase pathways. These differences may indicate an effect of air pollution during in utero life on the inflammatory state of the newborn at birth. Oxylipins may be important mediators between early life exposures and health outcomes later in life. Citation: Martens DS, Gouveia S, Madhloum N, Janssen BG, Plusquin M, Vanpoucke C, Lefebvre W, Forsberg B, Nording M, Nawrot TS. 2017. Neonatal cord blood oxylipins and exposure to particulate matter in the early-life environment: an ENVIRONAGE birth cohort study. Environ Health Perspect 125:691–698; http://dx.doi.org/10.1289/EHP291

Mother’s Pre-pregnancy BMI and Placental Candidate miRNAs: Findings from the ENVIR ON AGE Birth Cohort

There is increasing evidence that the predisposition for development of chronic diseases arises at the earliest times of life. In this context, maternal pre-pregnancy weight might modify fetal metabolism and the child’s predisposition to develop disease later in life. The aim of this study is to investigate the association between maternal pre-pregnancy body mass index (BMI) and miRNA alterations in placental tissue at birth. In 211 mother-newborn pairs from the ENVIRONAGE birth cohort, we assessed placental expression of seven miRNAs important in crucial cellular processes implicated in adipogenesis and/or obesity. Multiple linear regression models were used to address the associations between pre-pregnancy BMI and placental candidate miRNA expression. Maternal pre-pregnancy BMI averaged (±SD) 23.9 (±4.1) kg/m2. In newborn girls (not in boys) placental miR-20a, miR-34a and miR-222 expression was lower with higher maternal pre-pregnancy BMI. In addition, the association between maternal pre-pregnancy BMI and placental expression of these miRNAs in girls was modified by gestational weight gain. The lower expression of these miRNAs in placenta in association with pre-pregnancy BMI, was only evident in mothers with low weight gain (<14 kg). The placental expression of miR-20a, miR-34a, miR-146a, miR-210 and miR-222 may provide a sex-specific basis for epigenetic effects of pre-pregnancy BMI.

Cord plasma insulin and in utero exposure to ambient air pollution

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 mothers 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, newborns 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 PM2.5 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 PM10 exposure were similar with those of PM2.5 exposure but we did not observe an association between cord blood insulin levels and NO2 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/m3 (SD) increase in PM2.5 during pregnancy on cord plasma insulin levels corresponds to the effect-size of a 9kg/m2 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.

Ageing at the level of telomeres in association to residential landscape and air pollution at home and work: a review of the current evidence

Studies suggest that leukocyte telomere length is an index of systemic ageing. Here, we discuss telomere length as a marker of biological ageing in relation to residential landscape (greenness), residential air pollution and work-related exposures. Telomere lengths are memories of cumulative oxidative and inflammatory stress, and show to have inverse associations with the risk of non-communicable diseases. For this reason, telomeres are considered as markers of biological ageing. Studies at birth, in children, young adulthood, and elderly show that residential green space, lower traffic exposure and long-term lower exposure to particulate air pollution are associated with longer telomeres. Work-related exposures including exposure to toxic metals, polycyclic aromatic hydrocarbons and particulate matter are associated with shorter telomeres for a given age. In contrast to chronic exposures, evidence is present of the observation that recent exposure is associated with longer telomeres. Our overview shows that the magnitude of residential and work-related environmental factors on telomere length are often as important as many classical lifestyle factors.

Retinal microcirculation and leukocyte telomere length in the general population

Retinal arteriolar narrowing increases with age and predict adverse cardiovascular outcomes. Telomere length keeps track of the division of somatic cells and is a biomarker of biological age. We investigated to what extent retinal arteriolar diameters are associated with biological age, as captured by leukocyte telomere length (LTL). In 168 randomly selected Flemish participants from the family-based population study FLEMENGHO (mean age, 46.2 years) at baseline, of whom 85 underwent a follow-up examination (median, 4.1 years), we post-processed nonmydriatic retinal photographs and measured LTL. In men only, central retinal arteriolar equivalents (CRAE) and arteriole-to-venule ratio (AVR) were associated with LTL with stronger associations at higher age and body mass index. In men aged 57.6 years (75th percentile) a 20% shorter LTL was associated with a decrease in CRAE of 4.57 µm. A 20% shorter LTL was associated with a decrease of 5.88 µm in CRAE at a BMI of 29.9 kg/m2 (75th percentile). Similar associations were observed between AVR and LTL. In women, no retinal microvascular traits were associated with LTL. Retinal arteriolar narrowing in men but not in women is associated with biological age. Our findings support the idea that avoiding overweight contributes to maintaining a healthier microcirculation.

Author Correction: Mother’s Pre-pregnancy BMI and Placental Candidate miRNAs: Findings from the ENVIR ON AGE Birth Cohort

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A role for telomere length and chromosomal damage in idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis is a fatal lung disease characterized by a progressive formation of fibroblastic foci in the interstitium. This disease is strongly associated with telomere dysfunction but the extent of telomere shortening and consequent chromosomal damage within IPF lungs and with regional disease severity remains unknown.MethodsExplanted IPF lungs (n = 10) were collected from transplant surgeries with six samples per lung analysed to capture the regional heterogeneity ranging from mild to severe disease. Non-used donor lungs (n = 6) were collected as “healthy” controls. Structural changes related to disease severity (microCT surface density), relative telomere length (real-time qPCR), and quantitative histology of chromosomal damage (γ-H2A.X) and extracellular matrix (elastin, total collagen, collagen 1, and collagen 3) were measured. A multivariate linear mixed-effects model controlling for subject was used to identify association of disease severity or fibrotic markers with telomere length and chromosomal damage.ResultsWe observed shorter telomere length (p = 0.001) and increased chromosomal damage (p = 0.018) in IPF lungs compared to controls. In IPF lungs, telomere length was associated with total collagen (p < 0.001) but not with structural changes of disease severity. Chromosomal damage was positively associated with increased elastin (p = 0.006) and negatively with structural disease severity (p = 0.046). Extensive γ-H2A.X staining was also present in airway epithelial cells.ConclusionsTelomere length and chromosomal damage are involved in IPF with regional variation in telomere length and chromosomal damage associated with pathological changes in tissue structure and the extracellular matrix.