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BACKGROUND: Endocrine-disrupting chemicals may play a role in adiposity development during childhood. Until now literature in this scope suffers from methodologic limitations in exposure assessment using one or few urine samples and missing assessment during the infancy period. OBJECTIVES: We investigated the associations between early-life exposure to quickly metabolized chemicals and post-natal growth, relying on repeated within-subject urine collections over pregnancy and infancy. METHODS: We studied the associations of four phenols, four parabens, seven phthalates, and one nonphthalate plasticizer from weekly pooled urine samples collected from the mother during second and third trimesters (median 18 and 34 gestational weeks, respectively) and infant at 2 and 12 months of age, and child growth until 36 months. We relied on repeated measures of height, weight and head circumference from study visits and the child health booklet to predict growth outcomes at 3 and 36 months using the Jenss-Bayley nonlinear mixed model. We assessed associations with individual chemicals using adjusted linear regression and mixtures of chemicals using a Bayesian kernel machine regression model. RESULTS: The unipollutant analysis revealed few associations. Bisphenol S (BPS) at second trimester was positively associated with all infant growth parameters at 3 and 36 months, with similar patterns between exposure at third trimester and all infant growth parameters at 3 months. Mono-n-butyl phthalate (MnBP) at 12 months was positively associated with body mass index (BMI), weight, and head circumference at 36 months. Mixture analysis revealed positive associations between exposure at 12 months and BMI and weight at 36 months, with MnBP showing the highest effect size within the mixture. CONCLUSIONS: This study suggests that exposure in early infancy may be associated with increased weight and BMI in early childhood, which are risk factors of obesity in later life. Furthermore, this study highlighted the impact of BPS, a compound replacing bisphenol A, which has never been studied in this context. https://doi.org/10.1289/EHP13644, Introduction Phenols, parabens and phthalates are endocrine-disrupting chemicals (EDCs) used in plastics, lining of food cans, toys, and personal care products, among others. (1) Given their widespread use, exposure is [...]

Background: Endocrine disrupting compounds (EDCs) such as phthalates and phenols can affect placental functioning and fetal health, potentially via epigenetic modifications. We investigated the associations between pregnancy exposure to synthetic phenols and phthalates estimated from repeated urine sampling and genome wide placental DNA methylation. Methods: The study is based on 387 women with placental DNA methylation assessed with Infinium MethylationEPIC arrays and with 7 phenols, 13 phthalates, and two non-phthalate plasticizer metabolites measured in pools of urine samples collected twice during pregnancy. We conducted an exploratory analysis on individual CpGs (EWAS) and differentially methylated regions (DMRs) as well as a candidate analysis focusing on 20 previously identified CpGs. Sex-stratified analyses were also performed. Results: In the exploratory analysis, when both sexes were studied together no association was observed in the EWAS. In the sex-stratified analysis, 114 individual CpGs (68 in males, 46 in females) were differentially methylated, encompassing 74 genes (36 for males and 38 for females). We additionally identified 28 DMRs in the entire cohort, 40 for females and 42 for males. Associations were mostly positive (for DMRs: 93% positive associations in the entire cohort, 60% in the sex-stratified analysis), with the exception of several associations for bisphenols and DINCH metabolites that were negative. Biomarkers associated with most DMRs were parabens, DEHP, and DiNP metabolite concentrations. Some DMRs encompassed imprinted genes including APC (associated with parabens and DiNP metabolites), GNAS (bisphenols), ZIM2;PEG3;MIMT1 (parabens, monoethyl phthalate), and SGCE;PEG10 (parabens, DINCH metabolites). Terms related to adiposity, lipid and glucose metabolism, and cardiovascular function were among the enriched phenotypes associated with differentially methylated CpGs. The candidate analysis identified one CpG mapping to imprinted LGALS8 gene, negatively associated with ethylparaben. Conclusions: By combining improved exposure assessment and extensive placental epigenome coverage, we identified several novel genes associated with the exposure, possibly in a sex-specific manner.

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Background: Most previous studies investigating the associations between prenatal exposure to phthalates and fetal growth relied on measurements of phthalate metabolites at a single time point. They also focused on weight at birth without assessing growth over pregnancy, preventing the identification of potential periods of fetal vulnerability. We examined the associations between pregnancy urinary phthalate metabolites and fetal growth outcomes measured twice during pregnancy and at birth. Methods: For 484 pregnant women, we assessed 13 phthalate and two 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) metabolite concentrations from two within-subject weekly pools of up to 21 urine samples (median of 18 and 34 gestational weeks, respectively). Fetal biparietal diameter, femur length, head and abdominal circumferences were measured during two routine pregnancy follow-up ultrasonographies (median 22 and 32 gestational weeks, respectively) and estimated fetal weight (EFW) was calculated. Newborn weight, length, and head circumference were measured at birth. Associations between phthalate/DINCH metabolite and growth parameters were investigated using adjusted linear regression and Bayesian kernel machine regression models. Results: Detection rates were above 99 % for all phthalate/DINCH metabolites. While no association was observed with birth measurements, mono-iso-butyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP) were positively associated with most fetal growth parameters measured at the second trimester. Specifically, MiBP was positively associated with biparietal diameter, head and abdominal circumferences, while MnBP was positively associated with EFW, head and abdominal circumferences, with stronger associations among males. Pregnancy MnBP was positively associated with biparietal diameter and femur length at third trimester. Mixture of phthalate/DINCH metabolites was positively associated with EFW at second trimester. Conclusions: In this pregnancy cohort using repeated urine samples to assess exposure, MiBP and MnBP were associated with increased fetal growth parameters. Further investigation on the effects of phthalates on child health would be relevant for expanding current knowledge on their long-term effects.

Background: In vitro and toxicological studies have shown that non-persistent environmental chemicals can perturb thyroid hormone homeostasis. Epidemiological studies with improved exposure assessment (i.e., repeated urine samples) are needed to evaluate effects of these compounds, individually or as a mixture, in humans. We studied the associations between prenatal exposure to non-persistent environmental chemicals and neonatal thyroid hormones. Methods: The study population consisted of 442 mother–child pairs from the French SEPAGES mother–child cohort recruited between July 2014 and July 2017. For each participant, four parabens, five bisphenols, triclosan, triclocarban, benzophenone-3 as well as metabolites of phthalates and of di(isononyl)cyclohexane-1,2-dicarboxylate were assessed in two pools of repeated urine samples (median: 21 spot urines per pool), collected in the 2nd and 3rd trimesters of pregnancy, respectively. Thyroid stimulating hormone (TSH) and total thyroxine (T4) levels were determined in newborns from a heel-prick blood spot. Maternal iodine and selenium were assessed in urine and serum, respectively. Adjusted linear regression (uni-pollutant model) and Bayesian Kernel Machine Regression (BKMR, mixture model) were applied to study overall and sex-stratified associations between chemicals and hormone concentrations. Results: Interaction with child sex was detected for several compounds. Triclosan, three parabens, and one phthalate metabolite (OH-MPHP) were negatively associated with T4 among girls in the uni-pollutant model. BKMR also suggested a negative association between the mixture and T4 in girls, whereas in boys the association was positive. The mixture was not linked to TSH levels, and for this hormone the uni-pollutant model revealed associations with only a few compounds. Conclusion: Our study, based on repeated urine samples to assess exposure, showed that prenatal exposure to some phenols and phthalates disturb thyroid hormone homeostasis at birth. Furthermore, both uni-pollutant and mixture models, suggested effect modification by child sex, while, to date underlying mechanisms for such sex-differences are not well understood.

Background: Infancy perfluoroalkyl substances (PFAS) exposure from breastfeeding is partially determined by the transfer efficiencies (TEs) of PFAS from maternal serum into breast milk. However, to our knowledge there are no studies of such TEs in highly exposed populations. Objectives: We estimated the TEs of PFAS from maternal serum into colostrum and breast milk in a cohort of women with a wide range of PFAS exposures. Methods: The Ronneby Mother-Child Cohort was established in 2015 after PFAS contamination was discovered in the public drinking water of Ronneby, Sweden. We measured seven PFAS in matched samples of maternal serum at delivery and colostrum and breast milk. We calculated the TE (in percentage) as the ratio of PFAS in colostrum or breast milk to serum multiplied by 100 and evaluated whether TEs varied by PFAS, lactation stage, or exposure level using a series of linear mixed-effects models with a random intercept for each woman. Results: This study included 126 mothers. PFAS associated with firefighting foams [i.e., perfluorohexane sulfonic acid (PFHxS) and perfluorooctane sulfonic acid (PFOS)] were substantially elevated in the serum, colostrum, and breast milk samples of highly exposed women in the cohort and showed strong correlation. PFHxS and PFOS also contributed the largest fraction of total PFAS on average in colostrum and breast milk. Median TEs varied from 0.9% to 4.3% and were higher for perfluoroalkyl carboxylic acids, including perfluorooctanoic acid, than perfluoroalkane sulfonic acids, including PFHxS and PFOS. TEs varied by exposure level, but there was not a consistent pattern in this variation. Discussion: PFAS concentrations in the colostrum and breast milk of highly exposed women were higher than the concentrations in low-exposed women, and TEs were of a similar magnitude across exposure categories. This implies that breastfeeding may be an important route of PFAS exposure for breastfeeding infants with highly exposed mothers, although the relative contribution of breastfeeding vs. prenatal transplacental transfer remains to be clarified. https://doi.org/10.1289/EHP11292, Introduction Perfluoroalkyl substances (PFAS) are a diverse class of synthetic chemicals containing an aliphatic fluorinated carbon chain. (1) PFAS have unique chemical properties, including chemical and thermal stability and water [...]

Background Classical acupuncture is being used in the treatment of rheumatoid arthritis (RA). To explore the biological response to acupuncture, a network-based analysis was performed on gene expression data collected from an animal model of RA treated with acupuncture. Methods Gene expression data were obtained from published microarray studies on blood samples from rats with collagen induced arthritis (CIA) and non-CIA rats, both treated with manual acupuncture. The weighted gene co-expression network analysis was performed to identify gene clusters expressed in association with acupuncture treatment time and RA status. Gene ontology and pathway analyses were applied for functional annotation and network visualization. Results A cluster of 347 genes were identified that differentially downregulated expression in association with acupuncture treatment over time; specifically in rats with CIA with module-RA correlation at 1 hour after acupuncture (−0.27; p < 0.001) and at 34 days after acupuncture (−0.33; p < 0.001). Functional annotation showed highly significant enrichment of porphyrin-containing compound biosynthetic processes (p < 0.001). The network-based analysis also identified a module of 140 genes differentially expressed between CIA and non-CIA in rats (p < 0.001). This cluster of genes was enriched for antigen processing and presentation of exogenous peptide antigen (p < 0.001). Other functional gene clusters previously reported in earlier studies were also observed. Conclusion The identified gene expression networks and their hub-genes could help with the understanding of mechanisms involved in the pathogenesis of RA, as well understanding the effects of acupuncture treatment of RA.

Background: Studies characterizing associations between phenols, phthalates and thyroid hormones during pregnancy produce inconsistent results. This divergence may be partly attributable to false positives due to multiple comparison testing of large numbers of chemicals, and measurement error as studies rely on small numbers of biospecimens despite high intra-individual variability in urinary chemical metabolite concentrations. Objectives: This study employs a priori chemical filtering and expanded urinary biomonitoring to evaluate associations between phenol/phthalate exposures and serum thyroid hormones assessed during pregnancy. Methods: A two-tiered approach was implemented: a) In vitro high-throughput screening results from the ToxCast/Tox21 database, as informed by a thyroid Adverse Outcome Pathway network, were evaluated to select phenols/phthalates with activity on known and putative molecular initiating events in the thyroid pathway; and b) Adjusted linear regressions were used to study associations between filtered compounds and serum thyroid hormones measured in 437 pregnant women recruited in Grenoble area (France) between 2014 and 2017. Phenol/phthalate metabolites were measured in repeated spot urine sample pools (median: 21 samples/women). Results: The ToxCast/Tox21 screening reduced the chemical set from 16 to 13 and the associated number of statistical comparisons by 19%. Parabens were negatively associated with free triiodothyronine (T3) and the T3/T4 (total thyroxine) ratio. Monobenzyl phthalate was positively associated with total T4 and negatively with the T3/T4 ratio. Effect modification by iodine status was detected for several compounds (among them ZDEHP and mono-n-butyl phthalate) that were associated with some hormones among women with normal iodine levels. Conclusion: For these chemicals, screening for compounds with an increased likelihood for thyroid-related effects and relying on repeated urine samples to assess exposures improved the overall performance of multichemical analyses of thyroid disruption. This approach may improve future evaluations of human data for the thyroid pathway with implication for fetal health and may serve as a model for evaluating other toxicity outcomes. https://doi.org/10.1289/EHP10239, Introduction During pregnancy, euthyroidism is crucial for normal fetal growth and development. (1) Even subtle alterations of thyroid hormone homeostasis can negatively impact the growing fetus and postnatal health. (2) [...]

Background: Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects. Objectives: To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements. Methods: We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median = 21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother–child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5–5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions). Results: The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95 %CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95 %CI: −0.42, 3.81) and 1.17 points (95 %CI: −0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score. Discussion: Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds.

STUDY QUESTION Is exposure to environmental chemicals associated with modifications of placental morphology and function? SUMMARY ANSWER Phthalates, a class of ubiquitous chemicals, showed an association with altered placental weight, placental vascular resistance (PVR), and placental efficiency. WHAT IS KNOWN ALREADY Only a few epidemiological studies have assessed the effects of phenols and phthalates on placental health. Their results were affected by exposure measurement errors linked to the rapid excretion of these compounds and the reliance on a limited number of spot urine samples to assess exposure. STUDY DESIGN, SIZE, DURATION A prospective mother–child cohort, with improved exposure assessment for non-persistent chemicals, recruited participants between 2014 and 2017. Sample size ranged between 355 (placental parameters measured at birth: placental weight and placental-to-fetal weight ratio (PFR): a proxy for placental efficiency) and 426 (placental parameters measured during pregnancy: placental thickness and vascular resistance). PARTICIPANTS/MATERIALS, SETTING, METHODS Phenols (four parabens, two bisphenols, triclosan, and benzophenone-3), 13 phthalate metabolites, and two non-phthalate plasticizer metabolites were measured in within-subject pools of repeated urine samples collected during the second and third trimesters of pregnancy (median = 21 samples/trimester/woman). Placental thickness and PVR were measured during pregnancy. The placenta was weighed at birth and the PFR was computed. Both adjusted linear regression and Bayesian Kernel Machine Regression were used to evaluate associations between phenols and phthalates (alone or as a mixture) and placental parameters. Effect modification by child sex was also investigated. MAIN RESULTS AND THE ROLE OF CHANCE Several phthalate metabolites were negatively associated with placental outcomes. Monobenzyl phthalate (MBzP) concentrations, during the second and third trimesters of pregnancy, were associated with a decrease in both placental weight at birth (β = −20.1 g [95% CI: −37.8; −2.5] and β = −17.4 g [95% CI: −33.2; −1.6], for second and third trimester, respectively) and PFR (β = −0.5 [95% CI: −1, −0.1] and β = −0.5 [95% CI: −0.9, −0.1], for the second and third trimester, respectively). Additionally, MBzP was negatively associated with PVR during the third trimester (β = −0.9 [95% CI: −1.8; 0.1]). Mono-n-butyl phthalate (MnBP), was negatively associated with PVR in both trimesters (β = −1.3, 95% CI: [−2.3, −0.2], and β = −1.2, 95% CI: [−2.4, −0.03], for the second and third trimester, respectively). After stratification for child sex, Σ diisononyl phthalate (DiNP) (either second or third-trimester exposures, depending on the outcomes considered) was associated with decreased PVR in the third trimester, as well as decreased placental weight and PFR in males. No associations were observed for phenol biomarkers. LIMITATIONS, REASONS FOR CAUTION False positives cannot be ruled out. Therefore, chemicals that were associated with multiple outcomes (MnBP and DiNP) or reported in existing literature as associated with placental outcomes (MBzP) should be considered as the main results. WIDER IMPLICATIONS OF THE FINDINGS Our results are consistent with in vitro studies showing that phthalates target peroxisome proliferator-activated receptor γ, in the family of nuclear receptors involved in key placental development processes such as trophoblast proliferation, migration, and invasion. In addition to placental weight at birth, we studied placental parameters during pregnancy, which could provide a broader view of how environmental chemicals affect maternal–fetal exchanges over the course of pregnancy. Our findings contribute to the increasing evidence indicating adverse impacts of phthalate exposure on placental health. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the French Research Agency—ANR (MEMORI project ANR-21-CE34-0022). The SEPAGES cohort was supported by the European Research Council (N°311765-E-DOHaD), the European Community's Seventh Framework Programme (FP7/2007-206—N°308333-892 HELIX), the European Union's Horizon 2020 research and innovation programme (N° 874583 ATHLETE Project, N°825712 OBERON Project), the French Research Agency—ANR (PAPER project ANR-12-PDOC-0029-01, SHALCOH project ANR-14-CE21-0007, ANR-15-IDEX-02 and ANR-15-IDEX5, GUMME project ANR-18-CE36-005, ETAPE project ANR-18-CE36-0005—EDeN project ANR-19-CE36-0003-01), the French Agency for Food, Environmental and Occupational Health & Safety—ANSES (CNAP project EST-2016-121, PENDORE project EST-2016-121, HyPAxE project EST-2019/1/039, PENDALIRE project EST-2022-169), the Plan Cancer (Canc'Air project), the French Cancer Research Foundation Association de Recherche sur le Cancer—ARC, the French Endowment Fund AGIR for chronic diseases—APMC (projects PRENAPAR, LCI-FOT, DysCard), the French Endowment Fund for Respiratory Health, the French Fund—Fondation de France (CLIMATHES—00081169, SEPAGES 5–00099903, ELEMENTUM—00124527). N.J. was supported by a doctoral fellowship from the University Grenoble Alpes. V.M. was supported by a Sara Borrell postdoctoral research contract (CD22/00176), granted by Instituto de Salud Carlos III (Spain) and NextGenerationEU funds. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT02852499. [ABSTRACT FROM AUTHOR]

Background: Parabens, bisphenol A and triclosan have been forbidden or restricted in specific types of consumer goods in Europe and France. Limited biomonitoring data are available in France since the implementation of these regulations, and exposure data on infants is scarce worldwide. Understanding the predictors of phenol urinary concentrations will help identify potential targets for prevention. Aim: We described levels, variability and predictors of exposure to 12 phenols in pregnant women and infants recruited between 2014 and 2017 in a French couple-child cohort. Methods: Among 479 pregnant women and 150 of their infants, we studied phenol urinary concentrations in within-subject, within-period pools of repeated urine samples collected during the second and third trimesters of pregnancy (up to 42 samples per woman), at 2 months and 12 months (up to 14 samples per infant). Time trends and associations with demographic, protocol, occupational and behavioral factors were studied using interval censored models to accommodate for undetected and unquantified urine concentrations. Results: Detection rates were above 90% for bisphenol A, ethylparaben, methylparaben, benzophenone-3 and triclosan and below 5% for bisphenol AF, B, F and triclocarban. Median levels of bisphenol A, bisphenol S, methylparaben, ethylparaben and propylparaben at 12 months were similar or higher than during pregnancy. For pregnant women all phenols but benzophenone-3 and bisphenol S showed a linear decrease between 2014 and 2017 (p-values

Background: Exposure to multiple chemicals occurs daily through several routes; diet, inhalation and dermal contact. Real-life exposure assessment is needed to understand the risk. Therefore, a human biomonitoring (BM) study was performed to examine the plausibility of source-to-dose calculations for chemical mixtures in the Horizon 2020 EuroMix project. Objectives: To provide a detailed description of the design of the EuroMix BM study, and to present the initial results for urinary phenols and phthalates and to describe their exposure determinants from foods and personal care products (PCPs). Method: Adults (44 males and 100 females) kept detailed diaries on their food consumption, PCP use and handling of cash receipts. Urine samples were collected over the same 24-hour period. Urinary levels of four parabens, five bisphenols, oxybenzone/benzophenone-3 (OXBE), triclosan (TCS), triclocarban (TCC) and metabolites of eight phthalates and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) were analysed by ultra-high-performance liquid chromatography and tandem mass spectrometry. Multivariable linear regressions were performed between PCPs/food categories and each dependent chemical variable separately, and were only sex-stratified when an interactions between sex and the independent variable was significant. Results: The detection rate for the metabolites of phthalates and DINCH, and bisphenol A (BPA) and TCS in urine was 88–100%, while bisphenol S (BPS) and bisphenol F (BPF) were only found in 29% and 4% of the urine samples, respectively. Bisphenol B (BPB), bisphenol AF (BPAF) and TCC were not detected. Food groups associated with phenol exposure were meat, bread, beverages and butter and oil. Food determinants for phthalate exposure were sweets, butter and oil, fruit and berries and other foods. The only positive association between the use of PCPs and phenols was found between BPA and lip gloss/balm. Phthalate exposure was associated with the use of shower gel, hand cream (females), toothpaste, anti-wrinkle cream (females) and shaving products (males). Conclusion: The participants in the EuroMix BM study were exposed to a mixture of phenols and phthalates. A variety of food categories and PCPs were found to be possible sources of these chemicals. This indicates a complex pattern of exposure to numerous chemicals from multiple sources, depending on individual diet and PCP preferences. Keywords: Contaminants, Chemicals, Phenols, Phthalate, Bisphenol, Paraben, Biomonitoring, Food, Personal care products, 24-hour urine