Air pollution, white matter microstructure, and brain volumes: Periods of susceptibility from pregnancy to preadolescence.

Air pollution exposure during early-life is associated with altered brain development, but the precise periods of susceptibility are unknown. We aimed to investigate whether there are periods of susceptibility of air pollution between conception and preadolescence in relation to white matter microstructure and brain volumes at 9-12 years old. We used data of 3515 children from the Generation R Study, a population-based birth cohort from Rotterdam, the Netherlands (2002-2006). We estimated daily levels of nitrogen dioxide (NO2), and particulate matter (PM2.5 and PM2.5absorbance) at participants' homes during pregnancy and childhood using land-use regression models. Diffusion tensor and structural brain images were obtained when children were 9-12 years of age, and we calculated fractional anisotropy and mean diffusivity, and several brain structure volumes. We performed distributed lag non-linear modeling adjusting for socioeconomic and lifestyle characteristics. We observed specific periods of susceptibility to all air pollutants from conception to age 5 years in association with lower fractional anisotropy and higher mean diffusivity that survived correction for multiple testing (e.g., -0.85 fractional anisotropy (95%CI -1.43; -0.27) per 5 µg/m3 increase in PM2.5 between conception and 4 years of age). We also observed certain periods of susceptibility to some air pollutants in relation to global brain and some subcortical brain volumes, but only the association between PM2.5 and putamen survived correction for multiple testing (172 mm3 (95%CI 57; 286) per 5 µg/m3 increase in PM2.5 between 4 months and 1.8 year of age). This study suggested that conception, pregnancy, infancy, toddlerhood, and early childhood seem to be susceptible periods to air pollution exposure for the development of white matter microstructure and the putamen volume. Longitudinal studies with repeated brain outcome measurements are needed for understanding the trajectories and the long-term effects of exposure to air pollution.

Associations of Air Pollution on the Brain in Children: A Brain Imaging Study.

Introduction: Epidemiological studies are highlighting the negative effects of the exposure to air pollution on children's neurodevelopment. However, most studies assessed children's neurodevelopment using neuropsychological tests or questionnaires. Using magnetic resonance imaging (MRI) to precisely measure global and region-specific brain development would provide details of brain morphology and connectivity. This would help us understand the observed cognitive and behavioral changes related to air pollution exposure. Moreover, most studies assessed only a few air pollutants. This project investigates whether air pollution exposure to many pollutants during pregnancy and childhood is associated with the morphology and connectivity of the brain in school-age children and pre-adolescents. Methods: We used data from the Generation R Study, a population-based birth cohort set up in Rotterdam, the Netherlands in 2002-2006 (n = 9,610). We used land-use regression (LUR) models to estimate the levels of 14 air pollutants at participant's homes during pregnancy and childhood: nitrogen oxides (NOx), nitrogen dioxide (NO2), particulate matter with aerodynamic diameter ≤10 µm (PM10) or ≤2.5 µm (PM2.5), PM between 10 µm and 2.5 µm (PMCOARSE), absorbance of the PM2.5 fraction - a measure of soot (PM2.5absorbance), the composition of PM2.5 such as polycyclic aromatic hydrocarbons (PAHs), organic carbon (OC), copper (Cu), iron (Fe), silicon (Si), zinc (Zn), and the oxidative potential of PM2.5 evaluated using two acellular methods: dithiothreitol (OPDTT) and electron spin resonance (OPESR). We performed MRI measurements of structural morphology (i.e., brain volumes, cortical thickness, and cortical surface area) using T1-weighted images in 6- to 10-year-old school-age children and 9- to 12-year-old pre-adolescents, structural connectivity (i.e., white matter microstructure) using diffusion tensor imaging (DTI) in pre-adolescents, and functional connectivity (i.e., connectivity score between brain areas) using resting-state functional MRI (rs-fMRI) in pre-adolescents. We assessed cognitive function using the Developmental Neuropsychological Assessment test (NEPSY-II) in school-age children. For each outcome, we ran regression analysis adjusted for several socioeconomic and lifestyle characteristics. We performed single-pollutant analyses followed by multipollutant analyses using the deletion/substitution/addition (DSA) approach. Results: The project has air pollution and brain MRI data for 783 school-age children and 3,857 pre-adolescents. First, exposure to air pollution during pregnancy or childhood was not associated with global brain volumes (e.g., total brain, cortical gray matter, and cortical white matter) in school-age children or pre-adolescents. However, higher pregnancy or childhood exposure to several air pollutants was associated with a smaller corpus callosum and hippocampus, and a larger amygdala, nucleus accumbens, and cerebellum in pre-adolescents, but not in school-age children. Second, higher exposure to several air pollutants during pregnancy was associated with a thinner cortex in various regions of the brain in both school-age children and pre-adolescents. Higher exposure to air pollution during childhood was also associated with a thinner cortex in a single region in pre-adolescents. A thinner cortex in two regions mediated the association between higher exposure to air pollution during pregnancy and an impaired inhibitory control in school-age children. Third, higher exposure to air pollution during childhood was associated with smaller cortical surface areas in various regions of the brain except in a region where we observed a larger cortical surface area in pre-adolescents. In relation to brain structural connectivity, higher exposure to air pollution during pregnancy and childhood was associated with an alteration in white matter microstructure in pre-adolescents. In relation to brain functional connectivity, a higher exposure to air pollution, mainly during pregnancy and early childhood, was associated with a higher brain functional connectivity among several brain regions in pre-adolescents. Overall, we identified several air pollutants associated with brain structural morphology, structural connectivity, and functional connectivity, such as NOx, NO2, PM of various size fractions (i.e., PM10, PMCOARSE, and PM2.5), PM2.5absorbance, PAHs, OC, three elemental components of PM2.5 (i.e., Cu, Si, Zn), and the oxidative potential of PM2.5. Conclusions: The results of this project suggest that exposure to air pollution during pregnancy and childhood play an adverse role in brain development. We observed this relationship even at levels of exposure that were below the European Union legislations. We acknowledge that identifying the independent effects of specific pollutants was particularly challenging. Most of our conclusions generally refer to traffic-related air pollutants. However, we did identify pollutants specifically originating from brake linings, tire wear, and tailpipe emissions from diesel combustion. The current direction toward innovative solutions for cleaner energy vehicles is a step in the right direction. However, our findings indicate that these measures might not be completely adequate to mitigate health problems attributable to traffic-related air pollution, as we also observed associations with markers of brake linings and tire wear.

Exposure to traffic-related air pollution and noise during pregnancy and childhood, and functional brain connectivity in preadolescents.

BACKGROUND: The amount of people affected by traffic-related air pollution and noise is continuously increasing, but limited research has been conducted on the association between these environmental exposures and functional brain connectivity in children. OBJECTIVE: This exploratory study aimed to analyze the associations between the exposure to traffic-related air pollution and noise during pregnancy and childhood, and functional brain connectivity amongst a wide-swath of brain areas in preadolescents from 9 to 12 years of age. METHODS: We used data of 2,197 children from the Generation R Study. Land use regression models were applied to estimate nitrogen oxides and particulate matter levels at participant's homes for several time periods: pregnancy, birth to 3 years, 3 to 6 years, and 6 years of age to the age at magnetic resonance imaging (MRI) assessment. Existing noise maps were used to estimate road traffic noise exposure at participant's homes for the same time periods. Resting-state functional MRI was obtained at 9-12 years of age. Pair-wise correlation coefficients of the blood-oxygen-level-dependent signals between 380 brain areas were calculated. Linear regressions were run and corrected for multiple testing. RESULTS: Preadolescents exposed to higher levels of NO2, NOx, and PM2.5 absorbance, from birth to 3 years, and from 3 to 6 years of age showed higher correlation coefficients among several brain regions (e.g. from 0.16 to 0.19 higher correlation coefficient related to PM2.5 absorbance exposure, depending on the brain connection). Overall, most identified associations were between brain regions of the task positive and task negative networks, and were mainly inter-network (20 of 26). Slightly more than half of the connections were intra-hemispheric (14 of 26), predominantly in the right hemisphere. Road traffic noise was not associated with functional brain connectivity. CONCLUSIONS: This exploratory study found that exposure to traffic-related air pollution during the first years of life was related to higher functional brain connectivity predominantly in brain areas located in the task positive and task negative networks, in preadolescents from 9 to 12 years of age. These results could be an indicator of differential functional connectivity in children exposed to higher levels of air pollution.

Air pollution exposure during pregnancy and childhood and brain morphology in preadolescents.

BACKGROUND: Studies investigating the relationship between exposure to air pollution and brain development using magnetic resonance images are emerging. However, most studies have focused only on prenatal exposures, and have included a limited selection of pollutants. Here, we aim to expand the current knowledge by studying pregnancy and childhood exposure to a wide selection of pollutants, and brain morphology in preadolescents. METHODS: We used data from 3133 preadolescents from a birth cohort from Rotterdam, the Netherlands (enrollment: 2002-2006). Concentrations of nitrogen oxides, coarse, fine, and ultrafine particles, and composition of fine particles were estimated for participant's home addresses in pregnancy and childhood, using land use regression models. Structural brain images were obtained at age 9-12 years. We assessed the relationships of air pollution exposure, with brain volumes, and surface-based morphometric data, adjusting for socioeconomic and life-style characteristics, using single as well as multi-pollutant approach. RESULTS: No associations were observed between air pollution exposures and global volumes of total brain, and cortical and subcortical grey matter. However, we found associations between higher pregnancy and childhood air pollution exposures with smaller corpus callosum, smaller hippocampus, larger amygdala, smaller nucleus accumbens, and larger cerebellum (e.g. -69.2mm3 hippocampal volume [95%CI -129.1 to -9.3] per 1ng/m3 increase in pregnancy exposure to polycyclic aromatic hydrocarbons). Higher pregnancy exposure to air pollution was associated with smaller cortical thickness while higher childhood exposure was associated with predominantly larger cortical surface area. CONCLUSION: Higher pregnancy or childhood exposure to several air pollutants was associated with altered volume of several brain structures, as well as with cortical thickness and surface area. Associations showed some similarity to delayed maturation and effects of early-life stress.

Exposure to Air Pollution during Pregnancy and Childhood, and White Matter Microstructure in Preadolescents.

BACKGROUND: Air pollution has been related to brain structural alterations, but a relationship with white matter microstructure is unclear. OBJECTIVES: We assessed whether pregnancy and childhood exposures to air pollution are related to white matter microstructure in preadolescents. METHODS: We used data of 2,954 children from the Generation R Study, a population-based birth cohort from Rotterdam, Netherlands (2002-2006). Concentrations of 17 air pollutants including nitrogen oxides (NOX), particulate matter (PM), and components of PM were estimated at participants' homes during pregnancy and childhood using land-use regression models. Diffusion tensor images were obtained at child's 9-12 years of age, and fractional anisotropy (FA) and mean diffusivity (MD) were computed. We performed linear regressions adjusting for socioeconomic and lifestyle characteristics. Single-pollutant analyses were followed by multipollutant analyses using the Deletion/Substitution/Addition (DSA) algorithm. RESULTS: In the single-pollutant analyses, higher concentrations of several air pollutants during pregnancy or childhood were associated with significantly lower FA or higher MD (p<0.05). In multipollutant models of pregnancy exposures selected by DSA, higher concentration of fine particles was associated with significantly lower FA [-0.71 (95% CI: -1.26, -0.16) per 5 µg/m3 fine particles] and higher concentration of elemental silicon with significantly higher MD [0.06 (95% CI: 0.01, 0.11) per 100 ng/m3 silicon]. Multipollutant models of childhood exposures selected by DSA indicated significant associations of NOX with FA [-0.14 (95% CI: -0.23, -0.04) per 20-µg/m3 NOX increase], and of elemental zinc and the oxidative potential of PM with MD [0.03 (95% CI: 0.01, 0.04) per 10-ng/m3 zinc increase and 0.07 (95% CI: 0.00, 0.44) per 1-nmol DTT/min/m3 oxidative potential increase]. Mutually adjusted models of significant exposures during pregnancy and childhood indicated significant associations of silicon during pregnancy, and zinc during childhood, with MD. DISCUSSION: Exposure in pregnancy and childhood to air pollutants from tailpipe and non-tailpipe emissions were associated with lower FA and higher MD in white matter of preadolescents. https://doi.org/10.1289/EHP4709.

Prenatal and postnatal exposure to air pollution and emotional and aggressive symptoms in children from 8 European birth cohorts.

BACKGROUND: The association between air pollution exposure and emotional and behavioural problems in children is unclear. We aimed to assess prenatal and postnatal exposure to several air pollutants and child's depressive and anxiety symptoms, and aggressive symptoms in children of 7-11 years. METHODS: We analysed data of 13182 children from 8 European population-based birth cohorts. Concentrations of nitrogen dioxide (NO2), nitrogen oxides (NOx), particulate matter (PM) with diameters of ≤10 µm (PM10), ≤ 2.5 µm (PM2.5), and between 10 and 2.5 µm (PMcoarse), the absorbance of PM2.5 filters (PM2.5abs), and polycyclic aromatic hydrocarbons (PAHs) were estimated at residential addresses of each participant. Depressive and anxiety symptoms and aggressive symptoms were assessed at 7-11 years of age using parent reported tests. Children were classified in borderline/clinical range or clinical range using validated cut offs. Region specific models were adjusted for various socio-economic and lifestyle characteristics and then combined using random effect meta-analysis. Multiple imputation and inverse probability weighting methods were applied to correct for potential attrition bias. RESULTS: A total of 1896 (14.4%) children were classified as having depressive and anxiety symptoms in the borderline/clinical range, and 1778 (13.4%) as having aggressive symptoms in the borderline/clinical range. Overall, 1108 (8.4%) and 870 (6.6%) children were classified as having depressive and anxiety symptoms, and aggressive symptoms in the clinical range, respectively. Prenatal exposure to air pollution was not associated with depressive and anxiety symptoms in the borderline/clinical range (e.g. OR 1.02 [95%CI 0.95 to 1.10] per 10 µg/m3 higher NO2) nor with aggressive symptoms in the borderline/clinical range (e.g. OR 1.04 [95%CI 0.96 to 1.12] per 10 µg/m3 higher NO2). Similar results were observed for the symptoms in the clinical range, and for postnatal exposures to air pollution. CONCLUSIONS: Overall, our results suggest that prenatal and postnatal exposure to air pollution is not associated with depressive and anxiety symptoms or aggressive symptoms in children of 7 to 11 years old.

Air Pollution Exposure During Fetal Life, Brain Morphology, and Cognitive Function in School-Age Children.

BACKGROUND: Air pollution exposure during fetal life has been related to impaired child neurodevelopment, but it is unclear if brain structural alterations underlie this association. The authors assessed whether air pollution exposure during fetal life alters brain morphology and whether these alterations mediate the association between air pollution exposure during fetal life and cognitive function in school-age children. METHODS: We used data from a population-based birth cohort set up in Rotterdam, The Netherlands (2002-2006). Residential levels of air pollution during the entire fetal period were calculated using land-use regression models. Structural neuroimaging and cognitive function were performed at 6 to 10 years of age (n = 783). Models were adjusted for several socioeconomic and lifestyle characteristics. RESULTS: Mean fine particle levels were 20.2 µg/m3 (range, 16.8-28.1 µg/m3). Children exposed to higher particulate matter levels during fetal life had thinner cortex in several brain regions of both hemispheres (e.g., cerebral cortex of the precuneus region in the right hemisphere was 0.045 mm thinner (95% confidence interval, 0.028-0.062) for each 5-µg/m3 increase in fine particles). The reduced cerebral cortex in precuneus and rostral middle frontal regions partially mediated the association between exposure to fine particles and impaired inhibitory control. Air pollution exposure was not associated with global brain volumes. CONCLUSIONS: Exposure to fine particles during fetal life was related to child brain structural alterations of the cerebral cortex, and these alterations partially mediated the association between exposure to fine particles during fetal life and impaired child inhibitory control. Such cognitive impairment at early ages could have significant long-term consequences.

Exposure to elemental composition of outdoor PM2.5 at birth and cognitive and psychomotor function in childhood in four European birth cohorts.

BACKGROUND: Little is known about developmental neurotoxicity of particulate matter composition. We aimed to investigate associations between exposure to elemental composition of outdoor PM2.5 at birth and cognitive and psychomotor functions in childhood. METHODS: We analyzed data from 4 European population-based birth cohorts in the Netherlands, Germany, Italy and Spain, with recruitment in 2000-2006. Elemental composition of PM2.5 measurements were performed in each region in 2008-2011 and land use regression models were used to predict concentrations at participants' residential addresses at birth. We selected 8 elements (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc) and used principal component analysis to combine elements from the same sources. Cognitive (general, verbal, and non-verbal) and psychomotor (fine and gross) functions were assessed between 1 and 9years of age. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. RESULTS: 7246 children were included in this analysis. Single element analysis resulted in negative association between estimated airborne iron and fine motor function (-1.25 points [95% CI -2.45 to -0.06] per 100ng/m3 increase of iron). Association between the motorized traffic component, derived from principal component analysis, and fine motor function was not significant (-0.29 points [95% CI -0.64 to 0.06] per unit increase). None of the elements were associated with gross motor function or cognitive function, although the latter estimates were predominantly negative. CONCLUSION: Our results suggest that iron, a highly prevalent element in motorized traffic pollution, may be a neurotoxic compound. This raises concern given the ubiquity of motorized traffic air pollution.

Heat-related cardiovascular mortality risk in Cyprus: a case-crossover study using a distributed lag non-linear model.

BACKGROUND: The frequency and intensity of heat waves is projected to increase in many parts of the world, particularly in regions such as the Eastern Mediterranean and Middle East (EMME), where the warming trends are much larger than the global average. The relationship between air temperature and premature mortality is widely recognized, however, it is not well defined in the aforementioned region. The objective of this study is to assess the relationship between cardiovascular mortality risk and air temperature in Cyprus, an island located centrally in the EMME. METHODS: Daily cardiovascular mortality data and spatially aggregated daily mean, maximum, and minimum temperatures for the period 2004-2010 were analyzed using a case-crossover design combined with a distributed lag non-linear model. RESULTS: A relationship between high temperatures and cardiovascular mortality was observed for cerebrovascular diseases, ischaemic and other heart diseases; this relationship was exacerbated on days with high temperatures. The highest relative risk was observed on the day of the heat event and remained significantly elevated for another day. The results were consistent regardless whether the minimum, maximum, or mean temperatures were used, although the association seems to be more pronounced with the mean temperatures, which suggests that consecutive high day- and night-time temperatures are the most hazardous. CONCLUSIONS: The identification of a positive relationship between high temperatures and cardiovascular mortality in Cyprus raises concerns. In view of the projected climate changes and strong increases in extreme heat events in the region, appropriate interventions need to be developed.