Background and Aims Per‐ and polyfluoroalkyl substances (PFAS) are widespread and persistent pollutants that have been shown to have hepatotoxic effects in animal models. However, human evidence is scarce. We evaluated how prenatal exposure to PFAS associates with established serum biomarkers of liver injury and alterations in serum metabolome in children. Approach and Results We used data from 1,105 mothers and their children (median age, 8.2 years; interquartile range, 6.6‐9.1) from the European Human Early‐Life Exposome cohort (consisting of six existing population‐based birth cohorts in France, Greece, Lithuania, Norway, Spain, and the United Kingdom). We measured concentrations of perfluorooctane sulfonate, perfluorooctanoate, perfluorononanoate, perfluorohexane sulfonate, and perfluoroundecanoate in maternal blood. We assessed concentrations of alanine aminotransferase, aspartate aminotransferase, and gamma‐glutamyltransferase in child serum. Using Bayesian kernel machine regression, we found that higher exposure to PFAS during pregnancy was associated with higher liver enzyme levels in children. We also measured child serum metabolomics through a targeted assay and found significant perturbations in amino acid and glycerophospholipid metabolism associated with prenatal PFAS. A latent variable analysis identified a profile of children at high risk of liver injury (odds ratio, 1.56; 95% confidence interval, 1.21‐1.92) that was characterized by high prenatal exposure to PFAS and increased serum levels of branched‐chain amino acids (valine, leucine, and isoleucine), aromatic amino acids (tryptophan and phenylalanine), and glycerophospholipids (phosphatidylcholine [PC] aa C36:1 and Lyso‐PC a C18:1). Conclusions Developmental exposure to PFAS can contribute to pediatric liver injury.

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother–child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4–12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07–1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07–1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.

Few studies have investigated longitudinal associations between early life phthalate exposure and subsequent obesity and cardiovascular risks in children with inconsistent results. We aimed to evaluate the associations between phthalate exposure during gestation and childhood with offspring obesity and cardiometabolic risk factors in 500 mother-child pairs from the Rhea pregnancy cohort in Crete, Greece. Seven phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP)] were quantified in spot urine samples collected from mothers (1st trimester) and their children at 4 years of age. We calculated the molar sum of DEHP metabolites (MEHP, MEHHP, MEOHP). We measured child weight, height, waist circumference, skinfold thicknesses, blood pressure (BP), and lipids at 4 and 6 years and leptin, adiponectin, and C-reactive protein at 4 years. We used generalized estimating equations to examine associations at each age and tested for interaction by sex. Child exposure to phthalate metabolites was associated with lower BMI z-scores in boys and higher BMI z-scores in girls. Each 10-fold increase in ΣDEHP was associated with a change in waist circumference of −2.6 cm (95% CI: −4.72, −0.48) in boys vs. 2.14 cm (95% CI: −0.14, 4.43) in girls (p-sex interaction = 0.003) and a change in waist-to-height ratio of −0.01 (95% CI: −0.03, 0.01) in boys vs. 0.02 (95% CI: 0.01, 0.04) in girls (p-sex interaction = 0.006). Phthalate metabolite concentrations at age 4 were negatively associated with systolic and diastolic blood pressure. MEP was associated with lower systolic BP z-scores (adj. β = −0.22; 95% CI: −0.36, −0.08) at 4 years. MnBP and MBzP were associated with lower diastolic BP z-scores (adj. β = −0.13; 95%CI: −0.23, −0.04, and adj. β = −0.11; 95% CI: −0.21, −0.01, respectively). A 10-fold increase in MiBP was associated with 4.4% higher total cholesterol levels (95% CI: 0.2, 8.7). Prenatal phthalate exposure was not consistently associated with child adiposity and cardiometabolic measures. Our findings suggest that early life phthalate exposure may affect child growth and adiposity in a sex-specific manner and depends on the timing of exposure.

Animal studies suggest that prenatal vitamin D status may affect fetal brain growth. However, human studies are scarce with conflicting results. We aimed to investigate the association of maternal 25-hydroxyvitamin D [25(OH) D] levels with multiple neurodevelopmental outcomes at 4 years of age. We included 487 mother-child pairs from the prospective pregnancy cohort, "Rhea" in Crete, Greece. Maternal serum 25(OH) D concentrations were measured at the first prenatal visit (13 ± 2.4 weeks). Cognitive functions at 4 years were assessed by means of the McCarthy Scales of Children's Abilities. Behavioral difficulties were assessed by means of Strengths and Difficulties Questionnaire and Attention Deficit Hyperactivity Disorder Test. Children of women in the high 25(OH) D tertile (>50.7 nmol/l) had 37% decreased number of hyperactivity-impulsivity symptoms (IRR 0.63, 95% CI 0.39, 0.99, p = 0.05) and 40% decreased number of total ADHD-like symptoms (IRR 0.60, 95% CI 0.37, 0.95, p = 0.03) at 4 years of age, compared to children of women in the low 25(OH) D tertile (<38.4 nmol/l), after adjustment for several confounders. Similar associations were found with the hyperactivity/inattention score of the SDQ questionnaire. Children of mothers with high 25(OH) D levels had also fewer total behavioral difficulties (beta-coeff: -1.25, 95% CI -2.32, -0.19) and externalizing symptoms (beta-coeff: -0.87, 95% CI -1.58, -0.15) at preschool age. The observed associations were stronger in girls than in boys (p < 0.1). No association was observed between maternal 25(OH) D concentrations and cognitive function in preschoolers. Our results suggest that high maternal vitamin D levels in early pregnancy may protect against behavioral difficulties, especially ADHD-like symptoms at preschool age.

Background Child blood pressure (BP) is predictive of future cardiovascular risk. Prenatal exposure to metals has been associated with higher BP in childhood, but most studies have evaluated elements individually and measured BP at a single time point. We investigated impacts of prenatal metal mixture exposures on longitudinal changes in BP during childhood and elevated BP at 11 years of age. Methods The current study included 176 mother-child pairs from the Rhea Study in Heraklion, Greece and focused on eight elements (antimony, arsenic, cadmium, cobalt, lead, magnesium, molybdenum, selenium) measured in maternal urine samples collected during pregnancy (median gestational age at collection: 12 weeks). BP was measured at approximately 4, 6, and 11 years of age. Covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression and Bayesian Kernel Machine Regression (BKMR) were used to evaluate metal mixture impacts on baseline and longitudinal changes in BP (from ages 4 to 11) and the development of elevated BP at age 11, respectively. BKMR results were compared using static versus percentile-based cutoffs to define elevated BP. Results Molybdenum and lead were the mixture components most consistently associated with BP. J-shaped relationships were observed between molybdenum and both systolic and diastolic BP at age 4. Similar associations were identified for both molybdenum and lead in relation to elevated BP at age 11. For molybdenum concentrations above the inflection points (~ 40–80 μg/L), positive associations with BP at age 4 were stronger at high levels of lead. Lead was positively associated with BP measures at age 4, but only at high levels of molybdenum. Potential interactions between molybdenum and lead were also identified for BP at age 11, but were sensitive to the cutoffs used to define elevated BP. Conclusions Prenatal exposure to high levels of molybdenum and lead, particularly in combination, may contribute to higher BP at age 4. These early effects appear to persist throughout childhood, contributing to elevated BP in adolescence. Future studies are needed to identify the major sources of molybdenum and lead in this population.