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Experimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry and consumer products and bioaccumulate in food webs and human tissues, such as the liver. The objective of this study was to conduct a systematic review of the literature and meta-analysis evaluating PFAS exposure and evidence of liver injury from rodent and epidemiological studies. PubMed and Embase were searched for all studies from earliest available indexing year through 1 December 2021 using keywords corresponding to PFAS exposure and liver injury. For data synthesis, results were limited to studies in humans and rodents assessing the following indicators of liver injury: serum alanine aminotransferase (ALT), nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or steatosis. For human studies, at least three observational studies per PFAS were used to conduct a weighted -score meta-analysis to determine the direction and significance of associations. For rodent studies, data were synthesized to qualitatively summarize the direction and significance of effect. Our search yielded 85 rodent studies and 24 epidemiological studies, primarily of people from the United States. Studies focused primarily on legacy PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid. Meta-analyses of human studies revealed that higher ALT levels were associated with exposure to PFOA ( 6.20, ), PFOS ( 3.55, ), and PFNA ( 2.27, ). PFOA exposure was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in humans. In rodents, PFAS exposures consistently resulted in higher ALT levels and steatosis. There is consistent evidence for PFAS hepatotoxicity from rodent studies, supported by associations of PFAS and markers of liver function in observational human studies. This review identifies a need for additional research evaluating next-generation PFAS, mixtures, and early life exposures. https://doi.org/10.1289/EHP10092.

Purpose A growing body of evidence links poor maternal mental health with negative outcomes on early child development. We examined the effect of antenatal and postnatal maternal mental health on infant neurodevelopment at age 18 months in a population-based mother–child cohort (Rhea Study) in Crete, Greece. Methods Self-reported measures of maternal depression (EPDS), trait anxiety (STAI-Trait) and personality traits (EPQ-R) were assessed in a sample of women during pregnancy and at 8 weeks postpartum ( n  = 223). An additional sample of 247 mothers also completed the EPDS scale at 8 weeks postpartum ( n  = 470). Neurodevelopment at 18 months was assessed with the use of Bayley Scales of Infant and Toddler Development (3rd edition). Results Multivariable linear regression models adjusted for confounders revealed that antenatal depressive symptoms (EPDS ≥ 13) were associated with decrease in cognitive development independently of postnatal depression. High trait anxiety and extraversion were associated with decrease and increase, respectively, in social–emotional development. Also, high trait anxiety and neuroticism had a positive effect on infants’ expressive communication. Finally, postpartum depressive symptoms (EPDS ≥ 13) were associated with decrease in cognitive and fine motor development independently of antenatal depression. Conclusions These findings suggest that antenatal and postnatal maternal psychological well-being has important consequences on early child neurodevelopment.

Background:Pregnant women and children are especially vulnerable to exposures to food contaminants, and a balanced diet during these periods is critical for optimal nutritional status.Objectives:Our objective was to study the association between diet and measured blood and urinary levels of environmental contaminants in mother–child pairs from six European birth cohorts (n=818 mothers and 1,288 children).Methods:We assessed the consumption of seven food groups and the blood levels of organochlorine pesticides, polybrominated diphenyl ethers, polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFAS), and heavy metals and urinary levels of phthalate metabolites, phenolic compounds, and organophosphate pesticide (OP) metabolites. Organic food consumption during childhood was also studied. We applied multivariable linear regressions and targeted maximum likelihood based estimation (TMLE).Results:Maternal high (≥4  times/week) versus low (<2  times/week) fish consumption was associated with 15% higher PCBs [geometric mean (GM) ratio=1.15; 95% confidence interval (CI): 1.02, 1.29], 42% higher perfluoroundecanoate (PFUnDA) (GM   ratio=1.42; 95% CI: 1.20, 1.68), 89% higher mercury (Hg) (GM   ratio=1.89; 95% CI: 1.47, 2.41) and a 487% increase in arsenic (As) (GM   ratio=4.87; 95% CI: 2.57, 9.23) levels. In children, high (≥3  times/week) versus low (<1.5  times/week) fish consumption was associated with 23% higher perfluorononanoate (PFNA) (GM   ratio=1.23; 95% CI: 1.08, 1.40), 36% higher PFUnDA (GM   ratio=1.36; 95% CI: 1.12, 1.64), 37% higher perfluorooctane sulfonate (PFOS) (GM   ratio=1.37; 95% CI: 1.22, 1.54), and >200% higher Hg and As [GM   ratio=3.87 (95% CI: 1.91, 4.31) and GM   ratio=2.68 (95% CI: 2.23, 3.21)] concentrations. Using TMLE analysis, we estimated that fish consumption within the recommended 2–3 times/week resulted in lower PFAS, Hg, and As compared with higher consumption. Fruit consumption was positively associated with OP metabolites. Organic food consumption was negatively associated with OP metabolites.Discussion:Fish consumption is related to higher PFAS, Hg, and As exposures. In addition, fruit consumption is a source of exposure to OPs. https://doi-org.proxy.insermbiblio.inist.fr/10.1289/EHP5324

Cells can fine-tune which genes they activate, when and at which levels using a range of chemical marks on the DNA and certain proteins that help to organise the genome. One well-known example of such ‘epigenetic tags’ is DNA methylation, whereby a methyl group is added onto particular positions in the genome. Many factors – including environmental effects such as diet – control DNA methylation, allowing an organism to adapt to ever-changing conditions. An expression quantitative trait methylation (eQTM) is a specific position of the genome whose DNA methylation status regulates the activity of a given gene. A catalogue of eQTMs would be useful in helping to reveal how the environment and disease impacts the way cells work. Yet, currently, the relationships between most epigenetic tags and gene activity remains unclear, especially in children. To fill this gap, Ruiz-Arenas et al. studied DNA methylation in blood samples from over 800 healthy children across Europe. Amongst all tested DNA methylation sites, 22,000 (5.7% of total) were associated with the expression of a gene – and therefore were eQTMs; reciprocally, 9,000 genes (15.3% of all tested genes) were linked to at least one methylation site, leading to a total of 40,000 pairs of DNA methylation sites and genes. Most often, eQTMs regulated the expression of nearby genes – but only half controlled the gene that was the closest to them. Age and the genetic background of the individuals influenced the nature of eQTMs. This catalogue is a useful resource for the scientific community to start understanding the relationship between epigenetics and gene activity. Similar studies are now needed for other tissues and age ranges. Overall, extending our knowledge of eQTMs may help reveal how life events lead to illness, and could inform prevention efforts.

Background: During pregnancy, women are at particular risk for sleep deprivation and snoring because of the physiologic and hormonal changes of pregnancy. There is limited evidence for the association between sleep patterns in pregnancy and adverse birth outcomes. We examined the association of sleep duration and snoring in late pregnancy with the risk of preterm birth and fetal growth restriction. Methods: We used data from the prospective mother-child cohort \"Rhea\" study in Crete, Greece 2007-2009. The analysis included 1091 women with singleton pregnancies, providing complete data on sleeping habits at the third trimester of gestation and birth outcomes. Fetal growth restriction was based on a customized model, and multivariate log-binomial regression models were used to adjust for confounders. Results: Women with severe snoring were at high risk for low birth weight (relative risk = 2.6 [95% confidence interval = 1.2-5.4]), and fetal-growth-restricted neonates (2.0 [1.0-3.9]) after adjusting for maternal age, education, smoking during pregnancy, and prepregnancy body mass index (BMI). Women with sleep deprivation (≤5 hours sleep) were at high risk for preterm births (1.7 [1.1-2.8]), with the highest risk observed for medically indicated preterm births (2.4 [1.0-6.4]) after adjusting for maternal age, education, parity, smoking during pregnancy, and prepregnancy BMI. Conclusions: These findings suggest that women with severe snoring in late pregnancy have a higher risk for fetal-growth-restricted neonates; and women with sleep deprivation have a higher risk for preterm births. The mechanisms underlying these associations remain unclear.

Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes. We examined associations between PFAS exposure and glucose metabolism in youth. Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; ) participated in annual visits for an average of . Generalizability of findings were tested in young adults from the Southern California Children's Health Study (CHS; ) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography-high-resolution mass spectrometry; high levels were defined as concentrations percentile. In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels ( ) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had higher 60-min glucose (95% CI: ; ), higher 2-h glucose (95% CI: ; ), and 25% lower function ( ) compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had higher 60-min glucose (95% CI: ; ) and higher 2-h glucose, which did not meet statistical significance (95% CI: ; ). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism. Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200.

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 cohortspecific 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.

To discuss current evidence about the relation between prenatal and childhood Mediterranean diet, and the development of asthma and allergies in children. Review of the literature. Four recent studies conducted in Mediterranean countries (Spain, Greece) and one conducted in Mexico evaluated the association between childhood Mediterranean diet and asthma outcomes in children. All of the studies reported beneficial associations between a high level of adherence to the Mediterranean diet during childhood and symptoms of asthma or allergic rhinitis. Individual foods or food groups contributing to the protective effect of Mediterranean diet included fish, fruits, vegetables, legumes, nuts and cereals, while detrimental components included red meat, margarine and junk food intake. Two studies focused on prenatal Mediterranean diet: the first is a birth cohort in Spain that showed a protective effect of a high adherence to the Mediterranean diet during pregnancy on persistent wheeze, atopic wheeze and atopy at the age of 6.5 years; while the second is a cross-sectional study in Mexico, collecting information more than 6 years after pregnancy, that showed no associations between maternal Mediterranean diet during pregnancy and allergic symptoms in childhood except for current sneezing. Findings from recent studies suggest that a high level of adherence to the Mediterranean diet early in life protects against the development of asthma and atopy in children. Further studies are needed to better understand the mechanisms of this protective effect, to evaluate the most relevant window of exposure, and to address specific components of diet in relation to disease.

Background Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment–health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project ( http://www.projecthelix.eu ). Methods Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6–11) recruited from birth cohorts in six European countries were measured using high-throughput 1 H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates Absolute IDQ p180 kit). Results We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythronic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated ( r  > 0.18) between urine and serum. Conclusions We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children.

Maternal pre-pregnancy obesity may increase the risk of childhood obesity but it is unknown whether other metabolic factors in early pregnancy such as lipid profile and hypertension are associated with offspring cardiometabolic traits. Our objective was to investigate whether fasting lipid, glucose, and insulin levels during early pregnancy and maternal pre-pregnancy weight status, are associated with offspring adiposity measures, lipid levels and blood pressure at preschool age. The study included 618 mother-child pairs of the pregnancy cohort \"Rhea\" study in Crete, Greece. Pregnant women were recruited at the first prenatal visit (mean: 12 weeks, SD: 0.7). A subset of 348 women provided fasting serum samples for glucose and lipid measurements. Outcomes measures were body mass index, abdominal circumference, sum of skinfold thickness, and blood pressure measurements at 4 years of age. A subsample of 525 children provided non-fasting blood samples for lipid measurements. Pre-pregnancy overweight/obesity was associated with greater risk of offspring overweight/obesity (RR: 1.83, 95%CI: 1.19, 2.81), central adiposity (RR: 1.97, 95%CI: 1.11, 3.49), and greater fat mass by 5.10 mm (95%CI: 2.49, 7.71) at 4 years of age. These associations were more pronounced in girls. An increase of 40 mg/dl in fasting serum cholesterol levels in early pregnancy was associated with greater skinfold thickness by 3.30 mm (95%CI: 1.41, 5.20) at 4 years of age after adjusting for pre-pregnancy BMI and several other confounders. An increase of 10 mmHg in diastolic blood pressure in early pregnancy was associated with increased risk of offspring overweight/obesity (RR: 1.22, 95%CI: 1.03, 1.45), and greater skinfold thickness by 1.71 mm (95% CI: 0.57, 2.86) at 4 years of age. Metabolic dysregulation in early pregnancy may increase the risk of obesity at preschool age.