Search

Mitochondria are sensitive to oxidative stress, which can be caused by traffic-related air pollution. Placental mitochondrial DNA (mtDNA) mutations have been previously linked with air pollution. However, the relationship between prenatal air pollution and cord-blood mtDNA mutations has been poorly understood. Therefore, we hypothesized that prenatal particulate matter (PM 2.5 ) and NO 2 exposures are associated with cord-blood mtDNA heteroplasmy. As part of the ENVIR ON AGE cohort, 200 mother-newborn pairs were recruited. Cord-blood mitochondrial single-nucleotide polymorphisms were identified by whole mitochondrial genome sequencing, and heteroplasmy levels were evaluated based on the variant allele frequency (VAF). Outdoor PM 2.5 and NO 2 concentrations were determined by a high-resolution spatial-temporal interpolation method based on the maternal residential address. Distributed lag linear models were used to determine sensitive time windows for the association between NO 2 exposure and cord-blood mtDNA heteroplasmy. A 5 μg/m 3 increment in NO 2 was linked with MT-D-Loop 16311T>C heteroplasmy from gestational weeks 17-25. MT-CYTB 14766C>T was negatively associated with NO 2 exposure in mid pregnancy, from weeks 14-17, and positively associated in late pregnancy, from weeks 31-36. No significant associations were observed with prenatal PM 2.5 exposure. This is the first study to show that prenatal NO 2 exposure is associated with cord-blood mitochondrial mutations and suggests two critical windows of exposure in mid-to-late pregnancy.

Mechanisms underlying adverse birth and later in life health effects from exposure to air pollution during the prenatal period have not been not fully elucidated, especially in the context of mixtures. We assessed the effects of prenatal exposure to mixtures of air pollutants of particulate matter (PM), PM 2.5 , PM 10 , nitrogen oxides, NO 2 , NO x , ultrafine particles (UFP), and oxidative potential (OP) of PM 2.5 on infant birthweight in four European birth cohorts and the mechanistic underpinnings through cross-omics of metabolites and inflammatory proteins. The association between mixtures of air pollutants and birthweight z-scores (standardized for gestational age) was assessed for three different mixture models, using Bayesian machine kernel regression (BKMR). We determined the direct effect for PM 2.5 , PM 10 , NO 2 , and mediation by cross-omic signatures (identified using sparse partial least-squares regression) using causal mediation BKMR models. There was a negative association with birthweight z-scores and exposure to mixtures of air pollutants, where up to -0.21 or approximately a 96 g decrease in birthweight, comparing the 75th percentile to the median level of exposure to the air pollutant mixture could occur. Shifts in birthweight z-scores from prenatal exposure to PM 2.5 , PM 10 , and NO 2 were mediated by molecular mechanisms, represented by cross-omics scores. Interleukin-17 and epidermal growth factor were identified as important inflammatory responses underlyingair pollution-associated shifts in birthweight. Our results signify that by identifying mechanisms through which mixtures of air pollutants operate, the causality of air pollution-associated shifts in birthweight is better supported, substantiating the need for reducing exposure in vulnerable populations.

Mitochondrial DNA (mtDNA) content and telomere length are putative aging biomarkers and are sensitive to environmental stressors, including pollutants. Our objective was to identify, from a set of environmental exposures, which exposure is associated with leukocyte mtDNA content and telomere length in adults. This study includes 175 adults from 50 to 65 years old from the cross-sectional Flemish Environment and Health study, of whom leukocyte telomere length and mtDNA content were determined using qPCR. The levels of exposure of seven metals, 11 organohalogens, and four perfluorinated compounds (PFHxS, PFNA, PFOA, PFOS) were measured. We performed sparse partial least-squares regression analyses followed by ordinary least-squares regression to assess the multipollutant associations. While accounting for possible confounders and coexposures, we identified that urinary cadmium (6.52%, 95% confidence interval, 1.06, 12.28), serum hexachlorobenzene (2.89%, 018, 5.68), and perfluorooctanesulfonic acid (11.38%, 5.97, 17.08) exposure were positively associated ( p < 0.05) with mtDNA content, while urinary copper (-9.88%, -14.82, -4.66) and serum perfluorohexanesulfonic acid (-4.75%, -8.79, -0.54) exposure were inversely associated with mtDNA content. Urinary antimony (2.69%, 0.45, 4.99) and mercury (1.91%, 0.42, 3.43) exposure were positively associated with leukocyte telomere length, while urinary copper (-3.52%, -6.60, -0.34) and serum perfluorooctanesulfonic acid (-3.64%, -6.60, -0.60) showed an inverse association. Our findings support the hypothesis that environmental pollutants interact with molecular hallmarks of aging.

Maternal exposure to airborne particulate matter (PM) has been associated with restricted fetal growth and reduced birthweight. Here, we performed methylome-wide analyses of cord and children's blood DNA in relation to residential exposure to PM smaller than 10 μm (PM 10 ). This study included participants of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC, cord blood, n = 780; blood at age 7, n = 757 and age 15-17, n = 850) and the EXPOsOMICS birth cohort consortium including cord blood from ENVIR ONAGE ( n = 197), INMA ( n = 84), Piccolipiù ( n = 99) and Rhea ( n = 75). We could not identify significant CpG sites, by meta-analyzing associations between maternal PM 10 exposure during pregnancy and DNA methylation in cord blood, nor by studying DNA methylation and concordant annual exposure at 7 and 15-17 years. The CpG cg21785536 was inversely associated with PM 10 exposure using a longitudinal model integrating the three studied age groups (-1.2% per 10 μg/m 3 ; raw p-value = 3.82 × 10 -8 ). Pathway analyses on the corresponding genes of the 100 strongest associated CpG sites of the longitudinal model revealed enriched pathways relating to the GABAergic synapse, p53 signaling and NOTCH1. We provided evidence that residential PM 10 exposure in early life affects methylation of the CpG cg21785536 located on the EGF Domain Specific O-Linked N-Acetylglucosamine Transferase gene.