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Exposure to environmental factors, such as neurotoxic metals and micronutrients, during critical periods of development can contribute to long-term consequences in offspring's health, including neurodevelopmental outcomes. The aim of this study was to evaluate the association between simultaneous prenatal exposure to metals [lead (Pb), cadmium (Cd), mercury (Hg)] and micronutrients [selenium (Se), zinc (Zn), copper (Cu)] and neurodevelopmental outcomes in school-age children from the Polish Mother and Child Cohort (REPRO_PL). Metals and micronutrients concentrations were measured in cord blood (Pb, Cd, Se, Zn, Cu) and in maternal hair (Hg) collected during the 3rd trimester of pregnancy. Behavioral and emotional problems, as well as children's cognitive and psychomotor development, were assessed in 436 school-age children using the Strengths and Difficulties Questionnaire (SDQ, filled in by the mothers) and the Polish adaptation of the Intelligence and Development Scales (IDS, administered by trained psychologists). Multivariate regression models were applied after imputation of missing values, using two approaches: (i) a joint analysis taking into account all metals and micronutrients simultaneously, and (ii) an ExWAS study (single-exposure model). In the SDQ, Hyperactivity/Inattention problems and Total difficulties were associated with higher Hg concentrations in maternal hair (0.18, 95% CI: 0.05; 0.3; and 0.14, 95% CI: 0.01; 0.3, respectively), whereas Emotional symptoms were inversely associated with Se and Zn levels in cord blood (−0.13, 95% CI: −0.3; 0.004; and −0.10, 95% CI: −0.2; 0.02, respectively). In the IDS, cord blood Pb levels were found to be negatively associated with Fluid and Crystallized IQ (−0.12, 95% CI: −0.3; 0.02; and −0.14, 95% CI: −0.3; 0.007, respectively) as well as Mathematical skills (−0.15, 95% CI: −0.3; 0.01). The current research has been able to simultaneously assess the exposure to various interacting chemicals during the prenatal period. We demonstrate that prenatal co-exposures to Pb, Hg, Zn and Se have long-term influences on the neuropsychological outcome of school-age children.

The impact of maternal diet during pregnancy on the risk of allergic diseases in childhood is an increasing scientific and public health concern. We evaluated the associations of maternal type of diet and essential elements and vitamins intake during pregnancy with offspring allergic and respiratory outcomes.The study population included 557 mother-child pairs from Polish Mother and Child Cohort (REPRO_PL). Based on the Food Frequency Questionnaire filled in between the 20th-24th week of pregnancy, overall maternal diet was evaluated as the difference between the Prudent Dietary Pattern (PDP) score and Western Dietary Pattern (WDP) score ((PDP-WDP) score) and maternal achievement of dietary recommendations (estimated average requirement, EAR) for essential elements and vitamins was assessed. Children's health examination at age of 1, 2, and 7-9 years covered the following symptoms: infections, wheezing/asthma, food allergy, allergic rhinitis, and atopic dermatitis. At age of 7-9 years, children underwent spirometry and skin-prick tests.Children of the mothers who were not achieving adequate intake of vitamin C during pregnancy had a higher risk of wheezing and having more than two infections within the first two years of life comparing to those who met EAR (OR = 2.6, p = 0.05, and OR = 2.3, p = 0.04, respectively). Inadequate intake of vitamin E during pregnancy was related to a higher risk of atopic dermatitis (OR = 2.7, p = 0.04), whereas inadequate intake of magnesium during pregnancy was associated with the risk of wheezing in the offspring at age of two years (OR = 3.7, p = 0.03). A lower (PDP-WDP) score during pregnancy (indicating unhealthier diet) was associated with a higher risk of infections (OR = 1.5, p = 0.007) but a lower risk of atopic dermatitis (OR = 0.7, p = 0.02) at age of 7-9 years.These results may contribute to the body of evidence for the impact of maternal diet during pregnancy for children's optimal health, however further studies are needed before drawing conclusions and recommendations for clinical practice.

In this study, the exposome paradigm has been applied on a mother-child cohort adopting an optimised untargeted metabolomics approach for human urine followed by advanced bioinformatics analysis. Exposome-wide association algorithms were used to draw links between in utero co-exposure to metals and phthalates, metabolic pathways deregulation, and clinically observed phenotypes of neurodevelopmental disorders such as problems in linguistic, motor development and cognitive capacity. Children (n = 148) were tested at the first and second year of their life using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Their mothers had been exposed to metals and phthalates during the pregnancy, according to human biomonitoring results from previously performed studies. Untargeted metabolomics analysis of biobanked urine samples from the mothers was performed using a combination of the high throughput analytical methods liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance (NMR). Most perturbed metabolic pathways from co-exposure heavy metals and phthalates were pathways related to the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation, indicating the possibility of disruption of mitochondrial respiration. Overproduction of reactive oxygen species (ROS); the presence of glutathione peroxidase 3 (GPx3) during pregnancy and presence of glutathione peroxidase 1 (GPx1) in the umbilical cord were linked to verbal development problems. Another finding of the study is that in real life, adverse outcomes occur as a combination of environmental and social factors, all of them acting synergistically towards the deployment of an observed phenotype. Finally, the two-steps association process (exposure to pathways and pathways to adverse outcomes) was able to (a) provide associations that are not evident by directly associating exposure to outcomes and (b) provides additional insides on the mechanisms of environmental disease.

Phthalates are among the most frequently investigated environmental chemicals influencing children's health and particularly their neuropsychological development. However, the reported effects of these compounds on child behavior, cognitive and psychomotor outcomes are not fully consistent. The aim of this study is to evaluate the associations between prenatal and early postnatal phthalate exposures and child neurodevelopment at age of 7 years. A total of 134 mother-child pairs from Polish Mother and Child Cohort (REPRO_PL) constitute the basis for current analysis. Eleven phthalate metabolites were measured in urine samples collected from mothers in the 3rd trimester of pregnancy and from children at the age of 2 years. Child neuropsychological development at early school age (7 years) was assessed by both the Strengths and Difficulties Questionnaire (SDQ) filled by mothers and the Polish adaptation of the Intelligence and Development Scales (IDS) performed by psychologists. Mono-ethyl phthalate (MEP) concentration during pregnancy was significantly associated with increased risk of peer relationship problems in SDQ (OR = 2.7, p = 0.03). The results of the IDS analyses focused on child's cognitive and psychomotor development are not fully conclusive. Negative associations were evident between some phthalates in early childhood period and fluid intelligence and cognition (MEP: β = −5.2; p = 0.006; β = −4.2; p = 0.006; mono-n-butyl phthalate (MnBP): β = −4.9; p = 0.03; β = −4.0; p = 0.03; respectively), while positive associations have been found in the prenatal period (mono-2-ethyl-5-oxo-hexyl phthalate (oxo-MEHP): β = 3.6; p = 0.03 for fluid intelligence; β = 2.9; p = 0.03 for cognition). Further studies are required in order to elucidate which are the most critical periods of phthalate exposure on children's neurodevelopmental outcomes.

Characterization of the exposome, the totality of all environmental factors that one is exposed to from conception onwards, has been recommended to better evaluate the role of environmental influences on developmental programming and life- course vulnerability to major chronic diseases. In the framework of the Health and Environment- wide Associations based on Large population Surveys (HEALS) project we considered the pregnancy exposome exploiting two databases (PRIME and REPRO PL) that include birth cohorts from three EU countries (Croatia, Slovenia and Poland). The databases contained information on several chemical exposures, socio-demographic, lifestyle and health related factors from conception to child birth, and neuropsychological scores assessed by the Bayley Scales of Infant and Toddler Development in the first two years of life. Our main goal was to assess consistency of environmental influences on neurodevelopment, if any, across European countries differing for geographical, socio-demographic characteristics and levels of chemical exposures to metals such as lead (Pb), mercury (Hg), cadmium (Cd) and trace elements, including micronutrients such as zinc (Zn) and selenium (Se). To this aim, we first selected variables common to the different databases, then applied univariate and multivariate regression analyses to identify factors linked to neurodevelopment, and finally performed meta-analysis to detect potential heterogeneity among cohorts and pooled estimates. Significant differences in exposure levels among the three sub-cohorts were observed as for Hg and Se ; exposure levels under study were relatively low and within the range described in existing EU biomonitoring studies. The univariate analyses did not show any common pattern of association as only in the Polish cohort chemical exposure had an impact on neuropsychological outcome. In the meta-analysis, some consistent trends were evident, relative to the adverse influence of Pb on children's language and cognition and the positive influence of Se on language abilities. The effects of the neurotoxic metal Hg positively influenced the motor scores in the Polish cohorts, while it decreased the motor scores in the Slovenia and Croatian sub-cohorts. The only socio-demographic factor consistently associated to the outcome among cohorts was child's sex, with females performing better than males on cognitive and language scores. These findings point to the need of harmonizing existing cohorts or creating prospective study designs that facilitate comparisons in the exposome over time, places and kind of environmental exposures.

Some phthalates are known endocrine disrupting chemicals (EDC). They are widely present in the environment thus their impact on children’s health is of particular scientific interest. The aim of the study was to evaluate the association between phthalate exposure and neurodevelopmental outcomes, in particular behavioral, cognitive and psychomotor development, in 250 early school age children from the Polish Mother and Child Cohort (REPRO_PL). Urine samples were collected at the time of children’s neurodevelopmental assessment and were analysed for 21 metabolites of 11 parent phthalates. Behavioral and emotional problems were assessed by the Strengths and Difficulties Questionnaire (SDQ) filled in by the mothers. To assess children’s cognitive and psychomotor development, Polish adaptation of the Intelligence and Development Scales (IDS) was administered. The examination was performed by trained psychologists. Dimethyl phthalate (DMP) and di-n-butyl phthalate (DnBP) were the two phthalates showing the highest statistically significant associations, with higher total difficulties scores (β = 1.5, 95% CI 0.17; 2.7; β = 1.5, 95% CI 0.25; 2.8, respectively) as well as emotional symptoms and hyperactivity/inattention problems for DnBP (β = 0.46, 95% CI -0.024; 0.94; β = 0.72, 95% CI 0.065; 1.4, respectively), and peer relationships problems for DMP (β = 0.37, 95% CI -0.013; 0.76). In addition, DnBP and DMP have been found to be negatively associated with fluid IQ (β = −0.14, 95% CI -0.29; 0.0041) and crystallized IQ (β = −0.16, 95% CI -0.29; −0.025), respectively. In the case of mathematical skills, three phthalates, namely DMP (β = −0.17, 95% CI -0.31; −0.033), DEP (β = −0.16, 95% CI -0.29; −0.018) and DnBP (β = −0.14, 95% CI -0.28; 0.0012), have also shown statistically significant associations. This study indicates that exposure to some phthalates seems to be associated with adverse effects on behavioral and cognitive development of early school age children. Further action including legislation, educational and interventional activities to protect this vulnerable population is still needed.