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Background: Animal studies have linked prenatal poly- and perfluoroalkyl substances (PFAS) exposures with impaired placental structure and function. In humans, only few studies have investigated such associations. Objective: We studied whether PFAS, individually and as a mixture, affected placental function. Methods: In 367 pregnant women, we quantified 13 PFAS in serum collected at 19.3 gestational weeks (median). Placental weight was recorded at delivery. Histological examination of placental tissues allowed estimation of vascular perfusion (percentage of villi with syncytial knots, capillary density, intervillous space) and placental aging (fibrin deposition, calcification). Associations between PFAS and each of these parameters were assessed using adjusted linear, logistic regressions and mixture modeling through cluster analysis and Bayesian kernel machine regression (BKMR). Results: PFHxPA quantification (yes versus no) was associated with an increase in the percentages of villi with syncytial knots (β = 6.0% [95% CI: 1.1; 11]) and reduced intervillous spaces (β = 4.7% [95% CI: 0.1; 9.3]). A similar pattern was observed with PFHpA. Isolated associations were observed between PFTrDA and percentages of villi with syncytial knots (β = 8.6% [95% CI: 2.2; 15]) and 6:2diPAP and capillary density (β = −17% [95% CI: −30; −4.6]). Cluster analysis suggested that women in the moderate-to-higher PFAS exposure group had on average lower placental weight (β= −30 g [95% CI: −56; −4.3]), compared to those in the lower exposure group. Conclusions: Pregnancy PFAS levels were associated with placental parameters of fetal-maternal exchange, highlighting their broad physiological impacts.

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.

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: 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: 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