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Brain-derived neurotrophic factor (BDNF) and kisspeptin-1 (KISS-1) regulate placental development and fetal growth. The predictive value of maternal serum BDNF and KISS-1 concentrations for placental and umbilical cord levels has not yet been explored. The influence of prenatal lead (Pb) and cadmium (Cd) exposure and maternal iron status on BDNF and KISS-1 levels is also unclarified and of concern. In a pilot cross-sectional study with 65 mother–newborn pairs, we analyzed maternal and cord serum levels of pro-BDNF, mature BDNF, and KISS-1, BDNF, and KISS-1 gene expression in placenta, Pb and Cd in maternal and umbilical cord blood (erythrocytes), and placenta. We conducted a series of in vitro experiments using human primary trophoblast cells (hTCs) and BeWo cells to verify main findings of the epidemiological analysis. Strong and consistent correlations were observed between maternal serum levels of pro-BDNF, mature BDNF, and KISS-1 and corresponding levels in umbilical serum and placental tissue. Maternal red blood cell Pb levels were inversely correlated with serum and placental KISS-1 levels. Lower expression and release of KISS-1 was also observed in Pb-exposed BeWo cells. In vitro Pb exposure also reduced cellular BDNF levels. Cd-treated BeWo cells showed increased pro-BDNF levels. Low maternal iron status was positively associated with low BDNF levels. Iron-deficient hTCs and BeWo cells showed a consistent decrease in the release of mature BDNF. The correlations between maternal BDNF and KISS-1 levels, placental gene expression, and umbilical cord serum levels, respectively, indicate the strong potential of maternal serum as predictive matrix for BDNF and KISS-1 levels in placentas and fetal sera. Pb exposure and iron status modulate BDNF and KISS-1 levels, but a clear direction of modulations was not evident. The associations need to be confirmed in a larger sample and validated in terms of placental and neurodevelopmental function., HBM4EU Project from the European Union's Horizon 2020 Research and Innovation Program under Grant Agreement No. 733032

Methyl mercury (MeHg) is an organic highly toxic compound that is transported efficiently via the human placenta. Our previous data suggest that MeHg is taken up into placental cells by amino acid transporters while mercury export from placental cells mainly involves ATP binding cassette (ABC) transporters. We hypothesized that the ABC transporter multidrug resistance-associated protein (MRP)1 (ABCC1) plays an essential role in mercury export from the human placenta. Transwell transport studies with MRP1-overexpressing Madin-Darby Canine Kidney (MDCK)II cells confirmed the function of MRP1 in polarized mercury efflux. Consistent with this, siRNA-mediated MRP1 gene knockdown in the human placental cell line HTR-8/SVneo resulted in intracellular mercury accumulation, which was associated with reduced cell viability, accompanied by increased cytotoxicity, apoptosis, and oxidative stress as determined via the glutathione (GSH) status. In addition, the many sources claiming different localization of MRP1 in the placenta required a re-evaluation of its localization in placental tissue sections by immunofluorescence microscopy using an MRP1-specific antibody that was validated in-house. Taken together, our results show that (1) MRP1 preferentially mediates apical-to-basolateral mercury transport in epithelial cells, (2) MRP1 regulates the GSH status of placental cells, (3) MRP1 function has a decisive influence on the viability of placental cells exposed to low MeHg concentrations, and (4) the in situ localization of MRP1 corresponds to mercury transport from maternal circulation to the placenta and fetus. We conclude that MRP1 protects placental cells from MeHg-induced oxidative stress by exporting the toxic metal and by maintaining the placental cells' GSH status in equilibrium. Electronic supplementary material The online version of this article (10.1007/s00204-020-02900-5) contains supplementary material, which is available to authorized users.

Per- and polyfluorinated substances (PFAS), ubiquitously present in the environment and biota, are transferred to the fetus via the placenta. PFAS can be distinguished, among other things, by their different carbon chain lengths and functional groups. The aim of this study was to provide comprehensive evidence on PFAS transfer rates across the human placental barrier by means of a meta-analysis based upon a systematic review. The available literature up to April 2021 was reviewed and transplacental transfer efficiencies (TTEs) of PFAS assessed. A total of 39 studies reporting data on 20 PFAS were included in the systematic review. Of these, 20 studies with data on 19 compounds were included in the meta-analysis. Comprehensive Meta-Analysis (CMA v3.0) was used for quantitative, statistical analyses with random effects models. A curvilinear relationship was found with short and long chains of perfluorocarboxylic acids (PFCAs) exhibiting higher TTE than compounds with intermediate chain length. Among the less well studied PFAS, perfluorohexanoic acid (PFHxA), 6:2 fluorotelomersulfonic acid (6:2 FTS) and perfluorobutanoic acid (PFBA) stood out the most with a high TEEs. The dependence of TTEs on chain length and functional group is clearly shown in this first meta-analysis on PFAS transfer across the human placenta. More data on effects of less well studied PFAS in pregnant women and neonates are needed to assess the potential risk for fetal exposure.

Growing up on a cattle farm and consuming raw cow's milk protects against asthma and allergies. We expect a cattle-specific protein as active component in this farm effect.Dust was collected from cattle and poultry stables and from mattresses of households. Urine was obtained from cattle, and ambient aerosols were sampled. Samples were analysed for BLG by SDS PAGE/immunoblot and mass spectrometry, and for association with metals by SEC-ICP-MS. PBMC of healthy donors were incubated with BLG +/- zinc, and proliferation and cytokines determined. BALB/c mice were pre-treated intranasally with stable dust extract containing BLG or depleted of BLG, and subsequent allergy response after sensitization was evaluated on antibody and symptom level.A major protein in dust from cattle farms and ambient air was identified as BLG. Urine from female and male cattle is a major source of BLG. In dust samples, BLG was associated with zinc.The lipocalin BLG is found in large amounts in cattle urine, accumulates in bovine dust samples and is aerosolized around farms. Its association with zinc favorably shapes the human cellular immune response towards Th1-cytokines

Perfluorooctane sulfonic acid (PFOS) is a ubiquitous environmental pollutant. In humans, PFOS exposure has been associated with a number of adverse health outcomes, including reduced birth weight. Whether PFOS is capable of affecting angiogenesis and thus possibly fetal development is unknown. Therefore, we investigated 1) the metabolic activity of PFOS-exposed endothelial cells (human umbilical vein endothelial cells, HUVECs), fibroblasts (normal colon fibroblasts, NCFs), and epithelial cells (human colorectal carcinoma cells, HCT116), 2) PFOS-specific inhibition of vascular endothelial growth factor receptor (VEGFR)2 stimulation in KDR/NFAT-RE HEK293 cells, and 3) the antiangiogenic potential of PFOS in a 3D in vitro angiogenesis model of HUVECs and NCFs. In terms of metabolic activity, endothelial cells (HUVECs) were much more sensitive to PFOS than fibroblasts (NCFs) or epithelial cells (HCT116). VEGFR2 signaling in KDR/NFAT-RE HEK293 cells decreased with increasing PFOS concentrations. In co-culture (angiogenesis assay), PFOS treatment resulted in a dose-dependent reduction in tip and branch formation, tip length (μm), and total structural area (μm2) with stable metabolic activity of HUVECs up to high concentrations. We conclude that PFOS possesses antiangiogenic properties. Inhibition of VEGFR2 signaling indicates a possible mechanism of action that can be linked to an existing Adverse Outcome Pathway (AOP43) containing the AO reduced birth weight. Further studies are needed to confirm PFOS-specific adverse effects on angiogenesis, placental perfusion, and fetal growth.

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage.

Cadmium (Cd) is a global pollutant that accumulates in the placenta and can cause placental dysfunction. Although iron transporters have been suggested to participate in placental Cd uptake, it is still unknown which transporters are actually involved in this process. We specifically aimed to study the role of three iron transporters in the uptake of Cd into the placental cell line HTR-8/SVneo. For this purpose, Divalent Metal Transporter (DMT)1 and ZRT/IRT like protein (ZIP)8 and ZIP14 were downregulated and changes in cellular Cd levels analysed in relation to controls. As clearly shown by the reduction of the Cd content by ∼60% in DMT1- and ZIP14-downregulated cells, the two proteins are essential for Cd accumulation in HTR-8/SVneo cells. Using a validated antibody, we show DMT1 to be localised in situ in trophoblast and stromal cells. We further wanted to investigate how placental cells cope with Cd loading and which metallothionein (MT) isoforms they express. Cd-exposed cells accumulate Cd in a dose-dependent manner and upregulate MT2A accordingly (up to 15-fold induction upon 5 μM CdCl2 treatment for 72 h). 5 μM Cd exposure for 72 h decreased cell number to 60%, an effect that was aggravated by MT2A depletion (cell number reduced to 30%) indicating additive effects. In conclusion, our data suggest that DMT1 and ZIP14 are required for Cd uptake into human placental cells that upregulate MT2A to store and detoxify the metal. Cd storage in the placenta reduces Cd transport to the fetus, which, however, could impair placental functions and fetal development.

The organic mercury compound methylmercury (MeHg) is able to target the fetal brain. However, the uptake of the toxicant into placental cells is incompletely understood. MeHg strongly binds to thiol-S containing molecules such as cysteine. This MeHg-l-cysteine exhibits some structural similarity to methionine. System L plays a crucial role in placental transport of essential amino acids such as leucine and methionine and thus has been assumed to also transport MeHg-l-cysteine across the placenta. The uptake of methylmercury and tritiated leucine and methionine into the choriocarcinoma cell line BeWo was examined using transwell assay and small interfering (si)RNA mediated gene knockdown. Upon the downregulation of large neutral amino acids transporter (LAT)2 and 4F2 cell-surface antigen heavy chain (4F2hc), respectively, the levels of [3H]leucine in BeWo cells are significantly reduced compared to controls treated with non-targeting siRNA (p < 0.05). The uptake of [3H]methionine was reduced upon LAT2 down-regulation as well as methylmercury uptake after 4F2hc silencing (p < 0.05, respectively). These findings suggest an important role of system L in the placental uptake of the metal. Comparing the cellular accumulation of mercury, leucine, and methionine, it can be assumed that (1) MeHg is transported through system L amino acid transporters and (2) system L is responsible for the uptake of amino acids and MeHg primarily at the apical membrane of the trophoblast. The findings together can explain why mercury in contrast to other heavy metals such as lead or cadmium is efficiently transported to fetal blood.