International audience | In utero exposure to environmental chemicals, such as synthetic phenols, may alter DNA methylation in different tissues, including placenta - a critical organ for fetal development. We studied associations between prenatal urinary biomarker concentrations of synthetic phenols and placental DNA methylation. Our study involved 202 mother-son pairs from the French EDEN cohort. Nine phenols were measured in spot urine samples collected between 22 and 29 gestational weeks. We performed DNA methylation analysis of the fetal side of placental tissues using the IlluminaHM450 BeadChips. We evaluated methylation changes of individual CpGs in an adjusted epigenome-wide association study (EWAS) and identified differentially methylated regions (DMRs). We performed mediation analysis to test whether placental tissue heterogeneity mediated the association between urinary phenol concentrations and DNA methylation. We identified 46 significant DMRs (>= 5 CpGs) associated with triclosan (37 DMRs), 2,4-dichlorophenol (3), benzophenone-3 (3), methyl- (2) and propylparaben (1). All but 2 DMRs were positively associated with phenol concentrations. Out of the 46 identified DMRs, 7 (6 for triclosan) encompassed imprinted genes (APC, FOXG1, GNAS, GNASAS, MIR886, PEG10, SGCE), which represented a significant enrichment. Other identified DMRs encompassed genes encoding proteins responsible for cell signaling, transmembrane transport, cell adhesion, inflammatory, apoptotic and immunological response, genes encoding transcription factors, histones, tumor suppressors, genes involved in tumorigenesis and several cancer risk biomarkers. Mediation analysis suggested that placental cell heterogeneity may partly explain these associations. This is the first study describing the genome-wide modifications of placental DNA methylation associated with pregnancy exposure to synthetic phenols or their precursors. Our results suggest that cell heterogeneity might mediate the effects of triclosan exposure on placental DNA methylation. Additionally, the enrichment of imprinted genes within the DMRs suggests mechanisms by which certain exposures, mainly to triclosan, could affect fetal development.

The placenta is essential for sustaining the growth of the fetus. The aim of this study was to investigate the role of the placenta in MCLR-induced significant reduction in fetal weight, especially the changes in placental structure and function. Pregnant mice were intraperitoneally injected with MCLR (5 or 20 μg/kg) from gestational day (GD) 13 to GD17. The results showed MCLR reduced fetal weight and placenta weight. The histological specimens of the placentas were taken for light and electron microscopy studies. The internal space of blood vessels decreased obviously in the placental labyrinth layer of mice treated with MCLR. After the ultrastructural examination, the edema and intracytoplasmic vacuolization, dilation of the endoplasmic reticulum and corrugation of the nucleus were observed. In addition, maternal MCLR exposure caused a reduction of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) expression in placentae, a critical regulator of fetal development. Several genes of placental growth factors, such as Vegfα and Pgf and several genes of nutrient transport pumps, such as Glut1 and Pcft were depressed in placentas of MCLR-treated mice, however nutrient transporters Fatp1 and Snat4 were promoted. Moreover, significant increases in malondialdehyde (MDA) revealed the occurrence of oxidative stress caused by MCLR, which was also verified by remarkable decrease in the glutathione levels, total antioxidant capacity (T-AOC) as well as the activity of antioxidant enzymes. Real-time PCR and western blot analysis revealed that GRP78, CHOP, XBP-1, peIF2α and pIRE1 were remarkable increased in placentas of MCLR-treated mice, indicating that endoplasmic reticulum (ER) stress pathway was activated by MCLR. Furthermore, oxidative stress and ER stress consequently triggered apoptosis which contributed to the impairment of placental development. Collectively, these results suggest maternal MCLR exposure results in reduced fetal body weight, which might be associated with ROS-mediated endoplasmic reticulum stress and impairment in placental structure and function.

The knowledge about the effects of environmental temperature on human epigenome is a potential key to understand the health impacts of temperature and to guide acclimation under climate change. We performed a systematic review on the epidemiological studies that have evaluated the association between environmental temperature and human epigenetic modifications. We identified seven original articles on this topic published between 2009 and 2019, including six cohort studies and one cross-sectional study. They focused on DNA methylation in elderly people (blood sample) or infants (placenta sample), with sample size ranging from 306 to 1798. These studies were conducted in relatively low temperature setting (median/mean temperature: 0.8–13 °C), and linear models were used to evaluate temperature-DNA methylation association over short period (≤28 days). It has been reported that short-term ambient temperature could affect global human DNA methylation. A total of 15 candidate genes (ICAM-1, CRAT, F3, TLR-2, iNOS, ZKSCAN4, ZNF227, ZNF595, ZNF597, ZNF668, CACNA1H, AIRE, MYEOV2, NKX1-2 and CCDC15) with methylation status associated with ambient temperature have been identified. DNA methylation on ZKSCAN4, ICAM-1 partly mediated the effect of short-term cold temperature on high blood pressure and ICAM-1 protein (related to cardiovascular events), respectively. In summary, epidemiological evidence about the impacts of environment temperature on human epigenetics remains scarce and limited to short-term linear effect of cold temperature on DNA methylation in elderly people and infants. More studies are needed to broaden our understanding of temperature related epigenetic changes, especially under a changing climate.

Cadmium (Cd), a ubiquitous environmental pollutant, is known to impair placental development. However, the underlying mechanisms remain unclear. The present study used in vivo and in vitro models to investigate the effects of Cd on apoptosis and autophagy in placental trophoblasts and its mechanism. Pregnant mice were exposed to CdCl₂ (4.5 mg/kg) on gestational day (GD) 9. Human JEG-3 cells were exposed to CdCl₂ (0–40 μM) for different time points. Gestational Cd exposure obviously lowered the weight and diameter of mouse placentas. Number of TUNEL-positive cells was markedly elevated in Cd-administered mouse placentas and JEG-3 cells. Correspondingly, Cd significantly up-regulated cleaved caspase-3 protein level, a key indicator of apoptosis, in murine placentas and JEG-3 cells. Simultaneously, Cd also triggered autophagy, as determined by an elevation of LC3B-II and p62 protein, and accumulation of LC3-positive puncta, in placental trophoblasts. Chloroquine an autophagy inhibitor, obviously aggravated Cd-induced apoptosis in JEG-3 cells. By contrast, rapamycin, a specific autophagy inducer, significantly alleviated Cd-triggered apoptosis in JEG-3 cells. Mechanistically, autophagy inhibited Cd-induced apoptosis mainly via degrading caspase-9. Co-localizations of p62, a classical autophagic receptor, and caspase-9 were observed in Cd-stimulated human JEG-3 cells. Moreover, p62 siRNAs pretreatment markedly blocked the degradation of caspase 9 proteins via Cd-activated autophagy in JEG-3 cells. Collectively, our data suggest that activation of autophagy inhibits Cd-induced apoptosis via p62-mediated caspase-9 degradation in placental trophoblasts. These findings provide a new mechanistic insight into Cd-induced impairments of placental and fetal development.

Organochlorine pesticides (OCPs), including dichlorodiphenyltrichloroethane (DDT) and its metabolites [dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane], hexachlorocyclohexanes (HCHs), and hexachlorobenzene (HCB), are widely detected in humans despite the considerable decline in environmental concentrations. To understand the placental transfer of OCPs and the possible maternal influence on them, we measured the concentrations of DDTs, HCHs, and HCB in 102 paired samples of maternal and cord sera, and placentas collected in Shanghai, China. The median concentrations of DDTs and HCHs were the highest in maternal sera (601, 188 ng g⁻¹ lipid), followed by umbilical cord sera (389, 131 ng g⁻¹ lipid), and placentas (65, 37 ng g⁻¹ lipid). 4,4′-DDE, β-HCH, and HCB were the predominant contaminants in the three matrices. The ubiquitous existence of OCPs, and the significant concentration relationships of DDTs, HCHs, and OCPs in the three matrices suggested placental transfer from mother to fetus. The lipid-based concentration ratios of 4,4′-DDE, β-HCH, and HCB in umbilical cord serum to those in maternal serum (F/M), and ratios of placenta to maternal serum (P/M) ranged from 0.66 to 1.01, and 0.12 to 0.25, respectively. Maternal variables affected the levels of fetal contamination. For primiparous women, significant correlations between maternal age and maternal HCHs, and between pre-pregnancy body mass index (BMI) and maternal HCHs were found. The negative effect of parity, and the positive effect of food consumption on maternal OCP concentrations were also observed, although there were no significant differences. The possible influence of parity on F/M and P/M of 4,4′-DDE suggested borderline significant differences between primiparous and multiparous women. Also, slight group differences were observed between elder and younger women, and between overweight and normal/underweight women. Parity seems to have a potential influence on transfer ratios of some OCP pollutants.

Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) is a high-priority public health concern. However, maternal to fetal transplacental transfer of PAHs has not been systematically studied. To investigate the transplacental transfer of PAHs from mother to fetus and determine the influence of lipophilicity (octanol-water partition coefficient, KOW) on transfer process, in the present study, we measured the concentrations of 15 PAHs in 95 paired maternal and umbilical cord serum, and placenta samples (in total 285 samples) collected in Shanghai, China. The average concentration of total PAHs was the highest in maternal serums (1290 ng g−1 lipid), followed by umbilical cord serums (1150 ng g-1 lipid). The value was the lowest in placenta samples (673 ng g-1 lipid). Low molecular weight PAHs were the predominant compounds in the three matrices. Increases in fish and meat consumption did not lead to increases in maternal PAH levels, and no obvious gender differences in umbilical cord serums were observed. The widespread presence of PAHs in umbilical cord serums indicated the occurrence of transplacental transfer. The ratios of PAH concentrations in umbilical cord serum to those in maternal serum (F/M) and the concentrations in placenta to those in maternal serum (P/M) of paired samples were analyzed to characterize the transfer process of individual PAHs. Most F/M ratios on lipid basis were close to one (range: 0.79 to 1.36), which suggested that passive diffusion may control the transplacental transfer of PAHs from maternal serum to the fetal circulation. The P/M and F/M values calculated on lipid basis showed that PAHs with lower KOW were more likely to transfer from mother to fetus via the placenta.

The placenta is an intermediary organ between the female and the developing foetus. Some chemical substances, including the most harmful ones, exhibit the ability to accumulate in or penetrate through the placenta. The aim of the study was to determine the role of the placenta of the Baltic grey seal (Halichoerus grypus grypus) in the transfer of endocrine disrupting compounds (EDCs) - (bisphenol A, 4-tert- octylphenol, 4- nonylphenol), as well as total and organic mercury. 30 placentas were collected from grey seals pupping under human care at the Hel Marine Station in the years 2007–2016. The assays were conducted using the technique of high-preformance liquid chromatography (phenol derivatives) and atomic absorption spectrometry (mercury and selenium). A measurable level of EDCs was indicated in the placentas of grey seals. It was established that the inorganic Hg form was accumulated in the placenta, and that its concentrations were an order of magnitude higher than the concentrations of the organic form, which penetrated to the foetus. Similar observations were made for phenol derivatives - bisphenol A, 4-tert- octylphenol and 4-nonylphenol. For this compound group the placenta was a barrier, but the properties of phenol derivatives suggest the possibility of their penetration through this organ.

The western stock of the Steller sea lion (Eumetopias jubatus) in the northern Pacific Ocean has declined by approximately 80% over the past 30 years. This led to the listing of this sea lion population as an endangered species in 1997. Chemical pollution is a one of several contributing causes. In the present study, 145 individual PCBs were determined in tissues of male sea lions from Tatitlek (Prince William Sound) and St. Paul Island (Bering Sea), and placentae from the Aleutian Islands. PCBs 90/101, 118, and 153 were abundant in all the samples. The mean toxic equivalents (TEQ) were 2.6, 4.7 and 7.4pg/g lw in the kidney, liver, and blubber samples, respectively. The mean TEQ in placentae was 8pg/g lw. Total PCBs concentrations (2.6–7.9μg/g lw) in livers of some males were within a range known to cause physiological effects. Further suggesting the possibility of adverse effects on this stock.

Although studies have reported that polybrominated diphenyl ethers (PBDEs) can transfer from mothers to fetuses, the underlying transplacental transport and barrier mechanisms are still unclear. Therefore, we conducted a series of comprehensive experiments in humans, Sprague-Dawley rats, and a BeWo cell monolayer model, as well as a molecular docking study. PBDEs in mothers can transfer to fetuses with a ratio of approximately 0.46, suggesting that the placenta could not efficiently acts as a barrier to PBDE transplacental transport. Similar results were observed in pregnant rats, although varying times were required for different congeners to reach a steady-state in fetuses. The transport ratios at pregnancy day 14 in rats were generally higher than those at pregnancy day 18, which demonstrated that the barrier capacity of immature placentas was lower than that of mature placentas. None concentration-dependent transplacental transport was observed in BeWo cells with efflux ratios of 1.73–2.32, which suggested passive diffusion mechanisms govern the influx of PBDEs through placenta. The accumulated ratios of PBDEs and the inhibitor assay indicated that the effluent channel of P-glycoprotein was partially inhibited by PBDEs. Using molecular docking studies, three pocket sites were identified for different congeners in P-glycoprotein, which demonstrated that the inhibition of P-glycoprotein efflux pump through the pocket sites.

The ongoing transition to renewable fuel sources has led to increased use of wood and other biomass fuels. The physiochemical characteristics of biomass combustion derived aerosols depends on appliances, fuel and operation procedures, and particles generated during incomplete combustion are linked to toxicity. Frequent indoor wood burning is related to severe health problems such as negative effects on airways and inflammation, as well as chronic hypoxia and pathological changes in placentas, adverse pregnancy outcome, preterm delivery and increased risk of preeclampsia. The presence of combustion-derived black carbon particles at both the maternal and fetal side of placentas suggests that particles can reach the fetus. Air pollution particles have also been shown to inhibit trophoblast migration and invasion, which are vital functions for the development of the placenta during the first trimester. In this study we exposed a placental first trimester trophoblast cell line to wood smoke particles emitted under Nominal Burn rate (NB) or High Burn rate (HB). The particles were visible inside exposed cells and localized to the mitochondria, causing ultrastructural changes in mitochondria and endoplasmic reticulum. Exposed cells showed decreased secretion of the pregnancy marker human chorionic gonadotropin, increased secretion of IL-6, disrupted membrane integrity, disrupted proliferation and contained specific polycyclic aromatic hydrocarbons (PAHs) from the particles. Taken together, these results suggest that wood smoke particles can enter trophoblasts and have detrimental effects early in pregnancy by disrupting critical trophoblast functions needed for normal placenta development and function. This could contribute to the underlying mechanisms leading to pregnancy complications such as miscarriage, premature birth, preeclampsia and/or fetal growth restriction. This study support the general recommendation that more efficient combustion technologies and burning practices should be adopted to reduce some of the toxicity generated during wood burning.