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.

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.

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.

Perfluorooctanesulfonic acid (PFOS) is a ubiquitous environmental contaminant, previously utilized as a non-stick application for consumer products and firefighting foam. It can cross the placenta, and has been repeatedly associated with increased risk for diabetes in epidemiological studies. Here, we sought to establish the hazard posed by embryonic PFOS exposures on the developing pancreas in a model vertebrate embryo, and develop criteria for an adverse outcome pathway (AOP) framework to study the developmental origins of metabolic dysfunction. Zebrafish (Danio rerio) embryos were exposed to 16, 32, or 64 μM PFOS beginning at the mid-blastula transition. We assessed embryo health, size, and islet morphology in Tg(insulin-GFP) embryos at 48, 96 and 168 hpf, and pancreas length in Tg(ptf1a-GFP) embryos at 96 and 168 hpf. QPCR was used to measure gene expression of endocrine and exocrine hormones, digestive peptides, and transcription factors to determine whether these could be used as a predictive measure in an AOP. Embryos exposed to PFOS showed anomalous islet morphology and decreased islet size and pancreas length in a U-shaped dose-response curve, which resemble congenital defects associated with increased risk for diabetes in humans. Expression of genes encoding islet hormones and exocrine digestive peptides followed a similar pattern, as did total larval growth. Our results demonstrate that embryonic PFOS exposures can disrupt pancreatic organogenesis in ways that mimic human congenital defects known to predispose individuals to diabetes; however, future study of the association between these defects and metabolic dysfunction are needed to establish an improved AOP framework.

Dolphins are good bioindicators of the contamination status of marine ecosystems, since their dietary and habitat plasticity in both coastal and offshore ecotypes provide information on the trace elements levels originated from natural and anthropogenic sources. In this context, this study aimed to investigate provides mercury (Hg), selenium (Se) levels, trophic ecology and feeding environments of four small cetaceans (Tursiops truncatus, Steno bredanensis, Sotalia guianensis and Pontoporia blainvillei) inhabiting the central-northern coast of Rio de Janeiro State, southeastern Brazil. For the latter, δ15N and δ13C stable isotopes were used as indicators in this regard. Stable isotope values indicate that the four studied species have distinctive foraging habitats, coastal and least coastal, and occupy different trophic positions. The significant relationship found between muscle Hg and δ15N suggests that individual foraging preference remains relatively constant for the studied dolphin species over extended periods. The individual prey size and species are probably responsible for the differences found in Hg and Se concentrations in muscle tissue among all dolphin species. The vulnerable small coastal cetacean, P. blainvillei, which feeds on small teleost fish and squid, presented the lowest muscular Hg concentrations (less than 3.5 μg g−1 dry wt.). Meanwhile, S. bredanensis is more likely to uptake large amounts of trace elements among the four dolphin species, due to its feeding habits mainly being large offshore fish that accumulate high amounts of trace elements in organs and tissues. Differences found between Hg concentrations in fetus-mother pairs were much higher in S. guianensis than in P. blainvillei, suggesting that maternal contribution of Hg via placenta was more significant for the former.

Placenta and umbilical cord blood are important media for investigating maternal–fetal exposure to environmental pollutants. Historically hexachlorocyclohexanes (HCHs) were once widely-used in China. In this study, residues of HCHs were measured in placenta and umbilical cord blood samples for 40 women from Beijing. The measured median values of HCHs were 62.0 and 68.8 ng/g fat in placenta and umbilical cord blood, respectively. Concentrations of HCHs in placenta and umbilical cord blood of urban cohort were higher than those of rural group due to enhanced consumption of fish, meat, and milk. Residues of HCHs in placenta were significantly correlated with total food consumption, dietary intake, and maternal age, and could be predicted using the parameters dependent upon ingestion of meat and milk. The transplacental exposure of fetuses to HCHs was revealed by a close association between the residual levels in the paired placenta and the paired umbilical cord blood samples.

Perfluorooctane sulfonic acid (PFOS) is a persistent environmental pollutant. Exposure to PFOS has been associated with abnormal fetal development. The long non-coding RNA (lncRNA) has been showed to play a role in fetal growth restriction (FGR), preeclampsia (PE) and other pregnancy complications. Whether the lncRNA contributes to PFOS-induced toxicity in the placenta remains unknown. In this study, we investigated the function of lncRNA MEG3 and its derived miR-770 in PFOS-induced placental toxicity. Pregnant mice received gavage administration of different concentrations of PFOS (0.5, 2.5, and 12.5 mg/kg/day) from GD0 to GD17, and HTR-8/SVneo cells were treated with PFOS in the concentrations of 0, 10⁻¹, 1, 10 μM. We found that expression levels of miR-770 and its host gene MEG3 were reduced in mice placentas and HTR-8/SVneo cells with exposure of PFOS. A significant hypermethylation was observed at MEG3 promoter in placentas of mice gestational-treated with PFOS. We also confirmed that MEG3 and miR-770 overexpression alleviated the cell growth inhibition induced by PFOS. Furthermore, PTX3 (Pentraxin 3) was identified as the direct target of miR-770 and it was enhanced after PFOS exposure. In summary, our results suggested that MEG3 alleviate PFOS-induced placental cell inhibition through MEG3/miR-770/PTX3 axis.

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.