Association of exposure to mixture of chemicals during pregnancy with cognitive abilities and fine motor function of children.

Chemical exposures often occur in mixtures and exposures during pregnancy may lead to adverse effects on the fetal brain, potentially reducing lower cognitive abilities and fine motor function of the child. We investigated the association of mothers exposure to a mixture of chemicals during pregnancy (i.e., organochlorine compounds, per- and polyfluoroalkyl substances, phenols, phthalates, organophosphate pesticides) with cognitive abilties and fine motor function in their children. We studied 1097 mother-child pairs from five European cohorts participating in the Human Early Life Exposome study (HELIX). Measurement of 26 biomarkers of exposure to chemicals was performed on urine or blood samples of pregnant women (mean age 31 years). Cognitive abilities and fine motor function were assessed in their children (mean age 8 years) with a battery of computerized tests administered in person (Ravens Coloured Progressive Matrices, Attention Network Test, N-back Test, Trail Making Test, Finger Tapping Test). We estimated the joint effect of prenatal exposure to chemicals on cognitive abilities and fine motor function using the quantile-based g-computation method, adjusting for sociodemographic characteristics. A quartile increase in all the chemicals in the overall mixture was associated with worse fine motor function, specifically lower scores in the Finger Tapping Test [-8.5 points, 95 % confidence interval (CI) -13.6 to -3.4; -14.5 points, 95 % CI -22.4 to -6.6, and -18.0 points, 95 % CI -28.6 to -7.4) for the second, third and fourth quartile of the overal mixture, respectively, when compared to the first quartile]. Organochlorine compounds, phthalates, and per- and polyfluoroalkyl substances contributed most to this association. We did not find a relationship with cognitive abilities. We conclude that exposure to chemical mixtures during pregnancy may influence neurodevelopment, impacting fine motor function of the offspring.

Childhood exposure to outdoor air pollution in different microenvironments and cognitive and fine motor function in children from six European cohorts.

BACKGROUND: Exposure to air pollution during childhood has been linked with adverse effects on cognitive development and motor function. However, limited research has been done on the associations of air pollution exposure in different microenvironments such as home, school, or while commuting with these outcomes. OBJECTIVE: To analyze the association between childhood air pollution exposure in different microenvironments and cognitive and fine motor function from six European birth cohorts. METHODS: We included 1301 children from six European birth cohorts aged 6-11 years from the HELIX project. Average outdoor air pollutants concentrations (NO2, PM2.5) were estimated using land use regression models for different microenvironments (home, school, and commute), for 1-year before the outcome assessment. Attentional function, cognitive flexibility, non-verbal intelligence, and fine motor function were assessed using the Attention Network Test, Trail Making Test A and B, Raven Colored Progressive Matrices test, and the Finger Tapping test, respectively. Adjusted linear regressions models were run to determine the association between each air pollutant from each microenvironment on each outcome. RESULTS: In pooled analysis we observed high correlation (rs = 0.9) between air pollution exposures levels at home and school. However, the cohort-by-cohort analysis revealed correlations ranging from low to moderate. Air pollution exposure levels while commuting were higher than at home or school. Exposure to air pollution in the different microenvironments was not associated with working memory, attentional function, non-verbal intelligence, and fine motor function. Results remained consistently null in random-effects meta-analysis. CONCLUSIONS: No association was observed between outdoor air pollution exposure in different microenvironments (home, school, commute) and cognitive and fine motor function in children from six European birth cohorts. Future research should include a more detailed exposure assessment, considering personal measurements and time spent in different microenvironments.

Associations of gestational and early-life exposure to toxic metals and fluoride with a diagnosis of food allergy or atopic eczema at 1 year of age.

Studies have indicated that early-life exposure to toxic metals and fluoride affects the immune system, but evidence regarding their role in allergic disease development is scarce. We aimed to evaluate the relations of exposure to such compounds in 482 pregnant women and their infants (4 months of age) with food allergy and atopic eczema diagnosed by a paediatric allergologist at 1 year of age within the Swedish birth-cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Urinary cadmium and erythrocyte cadmium, lead, and mercury concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS), urinary inorganic arsenic metabolites by ICP-MS after separation by ion exchange chromatography, and urinary fluoride by an ion-selective electrode. The prevalence of food allergy and atopic eczema was 8 and 7%, respectively. Gestational urinary cadmium, reflecting chronic exposure, was associated with increased odds of infant food allergy (OR [95% CI]: 1.34 [1.09, 1.66] per IQR [0.08 µg/L]). Both gestational and infant urinary fluoride were associated, albeit at a statistically non-significant level, with increased atopic eczema odds (1.48 [0.98, 2.25], 1.36 [0.95, 1.95], per doubling, respectively). By contrast, gestational and infant erythrocyte lead was associated with decreased odds of atopic eczema (0.48 [0.26, 0.87] per IQR [6.6 µg/kg] and 0.38 [0.16, 0.91] per IQR [5.94 µg/kg], respectively), and infant lead with decreased odds of food allergy (0.39 [0.16, 0.93] per IQR [5.94 µg/kg]). Multivariable adjustment had marginal impact on the estimates above. After additional adjustment for fish intake biomarkers, the methylmercury associated atopic-eczema odds were considerably increased (1.29 [0.80, 2.06] per IQR [1.36 µg/kg]). In conclusion, our results indicate that gestational cadmium exposure might be associated with food allergy at 1 year of age and, possibly, early-life exposure to fluoride with atopic eczema. Further prospective and mechanistic studies are needed to establish causality.

Availability, accessibility, and use of green spaces and cognitive development in primary school children.

Green spaces may have beneficial impacts on children's cognition. However, few studies explored the exposure to green spaces beyond residential areas, and their availability, accessibility and uses at the same time. The aim of the present study was to describe patterns of availability, accessibility, and uses of green spaces among primary school children and to explore how these exposure dimensions are associated with cognitive development. Exposures to green space near home, school, commuting route, and other daily activity locations were assessed for 1607 children aged 6-11 years from six birth cohorts across Europe, and included variables related to: availability (NDVI buffers: 100, 300, 500 m), potential accessibility (proximity to a major green space: linear distance; within 300 m), and use (play time in green spaces: hours/year), and the number of visits to green spaces (times/previous week). Cognition measured as fluid intelligence, inattention, and working memory was assessed by computerized tests. We performed multiple linear regression analyses on pooled and imputed data adjusted for individual and area-level confounders. Availability, accessibility, and uses of green spaces showed a social gradient that was unfavorable in more vulnerable socioeconomic groups. NDVI was associated with more playing time in green spaces, but proximity to a major green space was not. Associations between green space exposures and cognitive function outcomes were not statistically significant in our overall study population. Stratification by socioeconomic variables showed that living within 300 m of a major green space was associated with improved working memory only in children in less deprived residential areas (ß = 0.30, CI: 0.09,0.51), and that more time playing in green spaces was associated with better working memory only in children of highly educated mothers (ß per IQR increase in hour/year = 0.10; 95% CI: 0.01, 0.19). However, studying within 300 m of a major green space increased inattention scores in children in more deprived areas (ß = 15.45, 95% CI: 3.50, 27.40).

Gestational and childhood urinary iodine concentrations and children's cognitive function in a longitudinal mother-child cohort in rural Bangladesh.

BACKGROUND: Severe iodine deficiency adversely affects neurodevelopment; however, evidence regarding the association of non-severe deficiency and child cognitive functioning is inconclusive. METHODS: This prospective mother-child cohort study was nested in a population-based nutritional supplementation trial in Bangladesh (Maternal and Infant Nutrition Interventions in Matlab [MINIMat]). Participants with data on cognitive abilities at 5 and 10 years of age (n = 1530) and at least one measurement of urinary iodine concentration (UIC) (gestational week 8, 5, and 10 years) were selected. Cognitive abilities were assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and Wechsler Intelligence Scale for Children (WISC-IV). UICs were measured with inductively coupled plasma mass spectrometry and thereafter adjusted for specific gravity. RESULTS: Median UICs in our population: (282 µg/L [pregnancy]; 406 µg/L [5 years]; 294 µg/L [10 years]) indicated that iodine intake corresponded to above 'adequate' or even 'excessive', according to the WHO classification. Maternal 'UIC <150 µg/L' was associated with lower full-scale and verbal scores at 5 and 10 years, although the associations were weakened in the fully adjusted models. A tendency of decreased verbal scores was also observed for maternal 'UIC ≥500 µg/L' but not for the corresponding child iodine category (≥300 µg/L). Child 'UIC <100 µg/L' was associated with lower processing speed (B=-3.1, 95% CI [-6.2, -0.1]; P-value = 0.041) compared with the reference group (100 µg/L≤ UIC <300 µg/L). CONCLUSIONS: Current findings add to the growing evidence of a causal association of early-life iodine intake with cognitive development, indicating that low iodine intake during childhood is associated with reduced processing speed and non-optimal gestational iodine intake is weakly associated with slightly poorer verbal development outcomes.

Maternal sleep disturbances during late pregnancy and child neuropsychological and behavioral development in early childhood.

The present study aims to explore the association of maternal sleep disturbances during late pregnancy on child neuropsychological and behavioral development in preschool years. The study included 638 mother-child pairs from the prospective Rhea mother-child cohort in Crete, Greece. Information on antenatal sleep disturbances was collected through a computer-assisted interview. Children's neuropsychological and behavioral development was assessed using the McCarthy Scales of Children's Abilities (MSCA), the Attention-Deficit Hyperactivity Disorder Test (ADHDT), and the Strengths and Difficulties Questionnaire (SDQ). Multivariate analysis showed that maternal sleep duration less than 8 h was associated with reduced scores in the general cognitive scale (ß = -2.28, 95% CI -4.54, -0.02, R2 = 0.417) and memory span (ß = -3.24, 95% CI -5.72, -0.77, R2 = 0.304), while mild-severe daytime sleepiness was associated with reduced scores in the memory scale (ß = -5.42, 95% CI -10.47, -0.37, R2 = 0.304), memory span (ß = -5.44, 95% CI -10.68, -0.21, R2 = 0.304), nd functions of posterior cortex (ß = -5.55, 95% CI -10.40, -0.70, R2 = 0.393) of MSCA. Snoring in late pregnancy was related to higher child hyperactivity scores in SDQ (ß = 1.05, 95% CI 0.16, 1.95, R2 = 0.160). An interaction between child sex and maternal sleep duration in response to ADHD symptoms was also found (p for interaction < 0.05). Stratified analysis revealed increased hyperactivity, inattention, and ADHD total scores for girls of mothers with sleep duration less than 8 h. Maternal sleep disturbances during pregnancy may be associated with impaired child neuropsychological and behavioral development during the preschool years. Early detection and intervention is necessary to reduce sleep disturbances habits in pregnancy and improve child neurodevelopment.

DNA methylation and general psychopathology in childhood: an epigenome-wide meta-analysis from the PACE consortium.

The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N = 2178 and N = 2190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p = 8.58 × 10-8). We also identified a significant differentially methylated region (DMR) at school-age (p = 1.63 × 10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.

Association of maternal urinary fluoride concentrations during pregnancy with size at birth and the potential mediation effect by maternal thyroid hormones: The Swedish NICE birth cohort.

BACKGROUND: Observational studies have indicated that elevated maternal fluoride exposure during pregnancy may impair child neurodevelopment but a potential impact on birth outcomes is understudied. OBJECTIVES: To evaluate the impact of gestational fluoride exposure on birth outcomes (birth size and gestational age at birth) and to assess the potential mediating role of maternal thyroid hormones. METHODS: We studied 583 mother-child dyads in the NICE cohort in northern Sweden. Maternal fluoride exposure was assessed by measuring urinary concentrations at late pregnancy (median: 29th gestational week) using an ion selective electrode. Plasma levels of free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH) were measured with electrochemiluminescence immunoassays. The infant's weight, length, head circumference, and gestational age at birth were extracted from hospital records. RESULTS: Median urinary fluoride concentration was 0.71 mg/L (5th-95th percentile 0.31-1.9 mg/L; specific gravity adjusted). In multivariable-adjusted regression models, every 1 mg/L increase of maternal urinary fluoride was associated with a mean increase in birth weight by 84 g (95%CI: 30, 138), length by 0.41 cm (95%CI: 0.18, 0.65), head circumference by 0.3 cm (95%CI: 0.1, 0.4), and with increased odds of being born large for gestational age (OR = 1.39, 95%CI: 1.03, 1.89). Every 1 mg/L increase of maternal urinary fluoride was also associated with a mean increase of the plasma fT3:fT4 ratio (B = 0.007, 95%CI: 0.000, 0.014), but not with the hormones or TSH. In mediation analyses, the maternal fT3:fT4 ratio did not explain the urinary fluoride-birth size relationships. DISCUSSION: Gestational urinary fluoride concentrations were associated with increased size at birth and even with increased odds of being born large for gestational age. The fluoride-related associations with increased size at birth were not explained by changes in maternal thyroid hormone levels.

Urban environment and cognitive and motor function in children from four European birth cohorts.

BACKGROUND: The urban environment may influence neurodevelopment from conception onwards, but there is no evaluation of the impact of multiple groups of exposures simultaneously. We investigated the association between early-life urban environment and cognitive and motor function in children. METHODS: We used data from 5403 mother-child pairs from four population-based birth-cohorts (UK, France, Spain, and Greece). We estimated thirteen urban home exposures during pregnancy and childhood, including: built environment, natural spaces, and air pollution. Verbal, non-verbal, gross motor, and fine motor functions were assessed using validated tests at five years old. We ran adjusted multi-exposure models using the Deletion-Substitution-Addition algorithm. RESULTS: Higher greenness exposure within 300 m during pregnancy was associated with higher verbal abilities (1.5 points (95% confidence interval 0.4, 2.7) per 0.20 unit increase in greenness). Higher connectivity density within 100 m and land use diversity during pregnancy were related to lower verbal abilities. Childhood exposure to PM2.5 mediated 74% of the association between greenness during childhood and verbal abilities. Higher exposure to PM2.5 during pregnancy was related to lower fine motor function (-1.2 points (-2.1, -0.4) per 3.2 µg/m3 increase in PM2.5). No associations were found with non-verbal abilities and gross motor function. DISCUSSION: This study suggests that built environment, greenness, and air pollution may impact child cognitive and motor function at five years old. This study adds evidence that well-designed urban planning may benefit children's cognitive and motor development.

The longitudinal association of eating behaviour and ADHD symptoms in school age children: a follow-up study in the RHEA cohort.

Previous evidence suggests a link between attention deficit hyperactivity disorder (ADHD) symptoms and disordered eating behaviours; however, the direction of the causal association remains unclear. Building on our previous research, we aimed to examine the longitudinal association between eating behaviours at 4 years, ADHD symptoms at 6 years of age, and the role of body mass index (BMI). We included children from the RHEA mother-child cohort in Greece, followed up at 4 and 6 years (n = 926). Parents completed the Children's Eating Behaviour Questionnaire (CEBQ) to assess children's eating behaviour at 4 years and the ADHD Test (ADHDT) and Child Behaviour Checklist for ages 6-18 (CBCL/6-18) to evaluate ADHD symptoms at 4 and 6 years, respectively, as well as measures of BMI. Longitudinal structural equation modeling (SEM) was carried out to evaluate the associations of all variables between 4 and 6 years. Food responsiveness at 4 years was positively associated with hyperactivity at age 6, whereas emotional overeating was negatively associated with hyperactivity. There was no evidence of an association between eating behaviours of preschoolers and BMI at 6 years, or BMI at 4 years and later ADHD symptoms and vice versa. Findings suggest that food responsiveness is an early marker of ADHD symptoms at 6 years of age. In contrast to our hypothesis there was no significant association between ADHD at age 4 and BMI at age 6.

Associations of exposure to cadmium, antimony, lead and their mixture with gestational thyroid homeostasis.

Maintaining thyroid homeostasis during pregnancy is vital for fetal development. The few studies that have investigated associations between metal exposure and gestational thyroid function have yielded mixed findings. To evaluate the association of exposure to a mixture of toxic metals with thyroid parameters in 824 pregnant women from the Rhea birth cohort in Crete, Greece. Concentrations of three toxic metals [cadmium (Cd), antimony (Sb), lead (Pb)] and iodine were measured in urine using inductively coupled plasma mass spectrometry and thyroid hormones [Thyroid Stimulating Hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3)] were measured in serum in early pregnancy. Associations of individual metals with thyroid parameters were assessed using adjusted regression models, while associations of the metal mixture with thyroid parameters were assessed using Bayesian Kernel Machine Regression (BKMR).Women with high (3rd tertile) concentrations of urinary Cd, Sb and Pb, respectively, had 13.3 % (95%CI: 2.0 %, 23.2 %), 12.5 % (95%CI: 1.8 %, 22.0 %) and 16.0 % (95%CI: 5.7 %, 25.2 %) lower TSH compared to women with low concentrations (2nd and 1st tertile). In addition, women with high urinary Cd had 2.2 % (95%CI: 0.0 %, 4.4 %) higher fT4 and 4.0 % (95%CI: -0.1 %, 8.1 %) higher fT3 levels, and women with high urinary Pb had 4 % (95%CI: 0.2 %, 8.0 %) higher fT3 levels compared to women with low exposure. The negative association of Cd with TSH persisted only when iodine sufficiency was unfavorable. BKMR attested that simultaneous exposure to toxic metals was associated with decreased TSH and increased fT3 and revealed a potential synergistic interaction of Cd and Pb in association with TSH. The present results suggest that exposure to toxic metals even at low levels can alter gestational thyroid homeostasis.

Early-life environmental exposure determinants of child behavior in Europe: A longitudinal, population-based study.

BACKGROUND: Environmental exposures in early life influence the development of behavioral outcomes in children, but research has not considered multiple exposures. We therefore aimed to investigate the impact of a broad spectrum of pre- and postnatal environmental exposures on child behavior. METHODS AND FINDINGS: We used data from the HELIX (Human Early Life Exposome) project, which was based on six longitudinal population-based birth cohorts in Europe. At 6-11 years, children underwent a follow-up to characterize their exposures and assess behavioral problems. We measured 88 prenatal and 123 childhood environmental factors, including outdoor, indoor, chemical, lifestyle and social exposures. Parent-reported behavioral problems included (1) internalizing, (2) externalizing scores, using the child behavior checklist (CBCL), and (3) the Conner's Attention Deficit Hyperactivity Disorder (ADHD) index, all outcomes being discrete raw counts. We applied LASSO penalized negative binomial regression models to identify which exposures were associated with the outcomes, while adjusting for co-exposures. In the 1287 children (mean age 8.0 years), 7.3% had a neuropsychiatric medical diagnosis according to parent's reports. During pregnancy, smoking and car traffic showing the strongest associations (e.g. smoking with ADHD index, aMR:1.31 [1.09; 1.59]) among the 13 exposures selected by LASSO, for at least one of the outcomes. During childhood, longer sleep duration, healthy diet and higher family social capital were associated with reduced scores whereas higher exposure to lead, copper, indoor air pollution, unhealthy diet were associated with increased scores. Unexpected decreases in behavioral scores were found with polychlorinated biphenyls (PCBs) and organophosphate (OP) pesticides. CONCLUSIONS: Our systematic exposome approach identified several environmental contaminants and healthy lifestyle habits that may influence behavioral problems in children. Modifying environmental exposures early in life may limit lifetime mental health risk.

Prenatal exposure to a wide range of environmental chemicals and child behaviour between 3 and 7 years of age - An exposome-based approach in 5 European cohorts.

BACKGROUND: Studies looking at associations between environmental chemicals and child behaviour usually consider only one exposure or family of exposures. OBJECTIVE: This study explores associations between prenatal exposure to a wide range of environmental chemicals and child behaviour. METHODS: We studied 708 mother-child pairs from five European cohorts recruited in 2003-2009. We assessed 47 exposure biomarkers from eight chemical exposure families in maternal blood or urine collected during pregnancy. We used the Strengths and Difficulties Questionnaire (SDQ) to evaluate child behaviour between three and seven years of age. We assessed associations of SDQ scores with exposures using an adjusted least absolute shrinkage and selection operator (LASSO) considering all exposures simultaneously and an adjusted exposome-wide association study (ExWAS) considering each exposure independently. RESULTS: LASSO selected only copper (Cu) as associated with externalizing behaviour. In the ExWAS, bisphenol A [BPA, incidence rate ratio (IRR): 1.06, 95% confidence interval (95%CI): 1.01;1.12] and mono-n-butyl phthalate (MnBP, IRR: 1.06, 95%CI: 1.00;1.13) were associated with greater risk of externalizing behaviour problems. Cu (IRR: 0.90, 95%CI: 0.82;0.98), perfluoroundecanoate (PFUnDA, IRR: 0.92, 95%CI: 0.84;0.99) and organochlorine compounds (OCs) were associated with lower risk of externalizing behaviour problems, however the associations with OCs were mainly seen among women with insufficient weight gain during pregnancy. Internalizing score worsen in association with exposure to diethyl thiophosphate (DETP, IRR: 1.11, 95%CI: 1.00;1.24) but the effect was driven by the smallest cohort. Internalizing score improved with increased concentration of perfluorooctane sulfonate (PFOS, IRR: 0.92, 95%CI: 0.85;1.00), however the association was driven by the two smallest cohorts with the lowest PFOS concentrations. DISCUSSION: This study added evidence on deleterious effects of prenatal exposure to BPA and MnBP on child behaviour. Other associations should be interpreted cautiously since they were not consistent with previous studies or they have not been studied extensively.

Maternal mild thyroid dysfunction and offspring cognitive and motor development from infancy to childhood: the Rhea mother-child cohort study in Crete, Greece.

BACKGROUND: Maternal thyroid hormones' supply is crucial for fetal neurodevelopment; however, the role of maternal mild thyroid dysfunction is not clear. We aimed to assess the association of maternal mild thyroid dysfunction with child neuropsychological development from infancy to early childhood. METHODS: We included 757 mother-child pairs from the prospective 'Rhea' cohort on Crete, Greece. Maternal thyroid functioning was assessed by quantitative analysis of serum thyroid-stimulating hormone, free thyroxine, thyroid peroxidase antibodies and thyroglobulin antibodies at early gestation (mean=14 weeks). Neuropsychological assessment was based on Bayley Scales of Infant Development (18 months of age), McCarthy Scales of Children's Abilities (4 years of age), Raven's Coloured Progressive Matrices, Trail Making Test and Finger Tapping Test (6 years of age). RESULTS: In multivariate adjusted linear regression analyses, maternal hypothyroxinemia was associated with decreased verbal scores at 4 years and reduced motor speed at 6 years of age. Maternal thyroid autoimmunity was associated with decreased child perceptual and motor ability at 4 years of age. Four trajectories of longitudinal non-verbal cognitive development were identified and children exposed to maternal thyroid autoimmunity had increased risk for belonging to an adverse trajectory ('low': adjusted relative risk ratio (RRR) = 2.7 95% CI: (1.4, 5.2), 'high-decreasing': adjusted RRR = 2.2 95% CI: (1.2, 4.0), 'low-increasing': adjusted RRR = 1.8 95% CI: (1.0, 3.2)). CONCLUSION: Maternal hypothyroxinemia is associated with reduced offspring verbal and motor ability. Maternal thyroid autoimmunity is associated with decreased offspring perceptual performance and motor ability and increased risk for adverse non-verbal cognitive development from infancy to childhood.

Cord Leptin is Associated with Neuropsychomotor Development in Childhood.

OBJECTIVE: Leptin is critical for central nervous system development and maturation. This study aimed to evaluate the potential regulatory role of cord leptin in the neuropsychomotor development of children ages 18 months to 6 years. METHODS: This study included 424 children from a prospective mother-child cohort (Rhea Study; Crete, Greece) with available cord leptin levels and data on neurodevelopmental outcomes at 18 months (Bayley Scales of Infant and Toddler Development, Third Edition), 4 years (McCarthy Scales of Children's Abilities), and 6 years (Raven's Coloured Progressive Matrices and Trail Making Test). Multivariable linear regression models were used to explore the associations. RESULTS: Each 10-ng/mL increase in the cord leptin level was associated with increased scores on the gross motor scale at 18 months (ß coefficient: 3.8; 95% CI: 0.0-7.5), with decreased scores in the general cognitive performance (ß coefficient: -3.0; 95% CI: -5.5 to -0.4), perceptual performance (ß coefficient: -3.4; 95% CI: -6.0 to -9.9), working memory (ß coefficient: -3.1; 95% CI: -5.7 to -0.4), executive function (ß coefficient -3.1; 95% CI: -5.7 to -0.5), and functions of the posterior cortex (ß coefficient: -2.7; 95% CI: -5.2 to -0.1) scales at 4 years, and with a 3.7-unit decrease in the Raven's Coloured Progressive Matrices score at 6 years (ß coefficient: -3.7; 95% CI: -6.9 to -0.5). CONCLUSIONS: Increased cord leptin levels are associated with enhanced gross motor development at 18 months but decreased cognitive performance in early and middle childhood.

Personal assessment of the external exposome during pregnancy and childhood in Europe.

The human exposome affects child development and health later in life, but its personal external levels, variability, and correlations are largely unknown. We characterized the personal external exposome of pregnant women and children in eight European cities. Panel studies included 167 pregnant women and 183 children (aged 6-11 years). A personal exposure monitoring kit composed of smartphone, accelerometer, ultraviolet (UV) dosimeter, and two air pollution monitors were used to monitor physical activity (PA), fine particulate matter (PM2.5), black carbon, traffic-related noise, UV-B radiation, and natural outdoor environments (NOE). 77% of women performed the adult recommendation of ≥150 min/week of moderate to vigorous PA (MVPA), while only 3% of children achieved the childhood recommendation of ≥60 min/day MVPA. 11% of women and 17% of children were exposed to daily PM2.5 levels higher than recommended (≥25µg/m3). Mean exposure to noise ranged from Lden 51.1 dB in Kaunas to Lden 65.2 dB in Barcelona. 4% of women and 23% of children exceeded the recommended maximum of 2 Standard-Erythemal-Dose of UV-B at least once a week. 33% of women and 43% of children never reached the minimum NOE contact recommendation of ≥30 min/week. The variations in air and noise pollution exposure were dominated by between-city variability, while most of the variation observed for NOE contact and PA was between-participants. The correlations between all personal exposures ranged from very low to low (Rho < 0.30). The levels of personal external exposures in both pregnant women and children are above the health recommendations, and there is little correlation between the different exposures. The assessment of the personal external exposome is feasible but sampling requires from one day to more than one year depending on exposure due to high variability between and within cities and participants.

Association between high levels of inflammatory markers and cognitive outcomes at 4 years of age: The Rhea mother-child cohort study, Crete, Greece.

There is growing evidence associating inflammatory markers in complex, higher order neurological functions, such as cognition and memory. We examined whether high levels of various inflammatory markers are associated with cognitive outcomes at 4 years of age in a mother-child cohort in Crete, Greece (Rhea study). We included 642 children in this cross-sectional study. Levels of several inflammatory markers (IFN-γ, IL-1ß, IL-6, IL-8, IL-17α, IL-10, MIP-1α, TNF-α and the ratios of IL-6 to IL-10 and TNF-α to IL-10) were determined in child serum via immunoassay. Neurodevelopment at 4 years was assessed by means of the McCarthy Scales of Children's Abilities. Multivariate linear regression analyses were used to estimate the associations between the exposures and outcomes of interest after adjustment for various confounders. Our results indicate that children with high TNF-α concentrations (≥90th percentile) in serum demonstrated decreased scores in memory (adjusted ß = -4.0; 95% CI: -7.7, -0.2), working memory (adjusted ß = -4.0; 95% CI: -8.0, -0.1) as well as in memory span scale (adjusted ß = -4.0; 95% CI: -7.9, -0.1). We also found that children with high IFN-γ serum levels showed lower scores in memory span scale (adjusted ß = -3.4; 95% CI: -7.3, -0.4). Children with elevated TNF-α/IL-10 ratio demonstrated decreased quantitative (adjusted ß = -4.3; 95% CI: -8.2, -0.4), motor (adjusted ß = -3.5; 95% CI: -7.5, -0.5), executive function (adjusted ß = -4.8; 95% CI: -8.5, -1.1), general cognitive (adjusted ß = -3.6; 95% CI: -7.3, -0.1), memory (adjusted ß = -3.8; 95% CI: -7.6, -0), working memory (adjusted ß = -3.5; 95% CI: -7.5, -0.5) and memory span scores (adjusted ß = -5.3; 95% CI: -9.1, -1.4) The findings suggest that high levels of TNF-α may contribute to reduced memory performance at preschool age.

Variability of urinary concentrations of non-persistent chemicals in pregnant women and school-aged children.

BACKGROUND: Exposome studies are challenged by exposure misclassification for non-persistent chemicals, whose temporal variability contributes to bias in dose-response functions. OBJECTIVES: We evaluated the variability of urinary concentrations of 24 non-persistent chemicals: 10 phthalate metabolites, 7 phenols, 6 organophosphate (OP) pesticide metabolites, and cotinine, between weeks from different pregnancy trimesters in pregnant women, and between days and between seasons in children. METHODS: 154 pregnant women and 152 children from six European countries were enrolled in 2014-2015. Pregnant women provided three urine samples over a day (morning, midday, and night), for one week in the 2nd and 3rd pregnancy trimesters. Children provided two urines a day (morning and night), over two one-week periods, six months apart. We pooled all samples for a given subject that were collected within a week. In children, we also made four daily pools (combining morning and night voids) during the last four days of the first follow-up week. Pools were analyzed for all 24 metabolites of interest. We calculated intraclass-correlation coefficients (ICC) and estimated the number of pools needed to obtain an ICC above 0.80. RESULTS: All phthalate metabolites and phenols were detected in >90% of pools whereas certain OP pesticide metabolites and cotinine were detected in <43% of pools. We observed fair (ICC = 0.40-0.59) to good (0.60-0.74) between-day reliability of the pools of two samples in children for all chemicals. Reliability was poor (<0.40) to fair between trimesters in pregnant women and between seasons in children. For most chemicals, three daily pools of two urines each (for weekly exposure windows) and four weekly pools of 15-20 urines each would be necessary to obtain an ICC above 0.80. CONCLUSIONS: This quantification of the variability of biomarker measurements of many non-persistent chemicals during several time windows shows that for many of these compounds a few dozen samples are required to accurately assess exposure over periods encompassing several trimesters or months.

The Urban Exposome during Pregnancy and Its Socioeconomic Determinants.

BACKGROUND: The urban exposome is the set of environmental factors that are experienced in the outdoor urban environment and that may influence child development. OBJECTIVE: The authors' goal was to describe the urban exposome among European pregnant women and understand its socioeconomic determinants. METHODS: Using geographic information systems, remote sensing and spatio-temporal modeling we estimated exposure during pregnancy to 28 environmental indicators in almost 30,000 women from six population-based birth cohorts, in nine urban areas from across Europe. Exposures included meteorological factors, air pollutants, traffic noise, traffic indicators, natural space, the built environment, public transport, facilities, and walkability. Socioeconomic position (SEP), assessed at both the area and individual level, was related to the exposome through an exposome-wide association study and principal component (PC) analysis. RESULTS: Mean±standard deviation (SD) NO2 levels ranged from 13.6±5.1 µg/m3 (in Heraklion, Crete) to 43.2±11 µg/m3 (in Sabadell, Spain), mean±SD walkability score ranged from 0.22±0.04 (Kaunas, Lithuania) to 0.32±0.07 (Valencia, Spain) and mean±SD Normalized Difference Vegetation Index ranged from 0.21±0.05 in Heraklion to 0.51±0.1 in Oslo, Norway. Four PCs explained more than half of variation in the urban exposome. There was considerable heterogeneity in social patterning of the urban exposome across cities. For example, high-SEP (based on family education) women lived in greener, less noisy, and less polluted areas in Bradford, UK (0.39 higher PC1 score, 95% confidence interval (CI): 0.31, 0.47), but the reverse was observed in Oslo (-0.57 PC1 score, 95% CI: -0.73, -0.41). For most cities, effects were stronger when SEP was assessed at the area level: In Bradford, women living in high SEP areas had a 1.34 higher average PC1 score (95% CI: 1.21, 1.48). CONCLUSIONS: The urban exposome showed considerable variability across Europe. Pregnant women of low SEP were exposed to higher levels of environmental hazards in some cities, but not others, which may contribute to inequities in child health and development. https://doi.org/10.1289/EHP2862.