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Introduction: Parabens are a group of chemicals widely used as preservatives in daily consumer products such as cosmetics, food items, pharmaceuticals and household commodities. They have been broadly detected in human samples indicating a general human exposure, and concerns arose from their potential endocrine disrupting effect. Especially the exposure to parabens during pregnancy is concerning, as the time of fetal development is a particularly vulnerable period. The aim of this study was to investigate the transport and metabolism of four commonly used parabens: methyl-, ethyl-, propyl- and butylparaben (MeP, EtP, PrP and BuP) and the metabolite para-hydroxybenzoic acid (PHBA) across the human placenta.Methods: An ex-vivo human placental perfusion model was used. The test compounds were added in the maternal compartment (with initial concentrations of 1 mM or 0.1 mM). Placental transport was evaluated by fetal-maternal concentration ratios (FM-ratio), transport index (TI) and indicative permeability (IP).Results: Information about parabens kinetics was taken from 10 perfusions and PHBA from 7 perfusions. Paraben metabolism was not detected. The placental transport of MeP, EtP, PrP, BuP and PHBA revealed a transfer from maternal to fetal circulations with FM120 of 0.86 ± 0.27 (MeP), 0.98 ± 0.28 (EtP), 1.00 ± 0.28 (PrP), 1.12 ± 0.59 (BuP) and 0.82 ± 0.37 (PHBA). The test substances accumulated in the perfused tissue in some degree. The average kinetic parameters FM-ratio, TI and IP were not different between chemicals.Discussion: The present study shows that the placenta barrier is permeable to all four parabens and the metabolite, which implies potential fetal exposure. [ABSTRACT FROM AUTHOR]

Introduction: The burden of environmental chemicals in the human population is ubiquitous and especially problematic in pregnancy due to potential exposure of the vulnerable fetus. According to the Developmental Origins of Health and Disease hypothesis, the fetal period is highly sensitive to exposure to environmental factors that will determine the development of diseases later in life. A range of environmental chemicals has been studied in the ex vivo placental perfusion model, which is a human model using the intact placenta directly after birth to study the placental transfer and metabolism of selected compounds.Methods: Here, we reviewed the existing knowledge on human placental perfusion of environmental chemicals in order to identify potential correlations between placental transfer and properties of chemicals and areas of future research needs.Results: We found 32 studies of the following groups of environmental chemicals: pesticides, persistent organic pollutants (POPs), plastics and byproducts, phyto/myco-estrogens and fungal toxins, byproducts from heating/curing food, combustion in traffic and industry, and metals. The studies showed highly distinct transfer rates from very fast transport to the fetal side to negligible transfer.Discussion: In general, a low molecular weight favors placental translocation, but placental translocation is dependent on other physicochemical properties of the substances, claiming the need for more standardized studies and proper quantitative structure-activity relationship (QSAR) analysis. Overall, we recommend using placental perfusion studies in the risk assessment of environmental toxicants, to determine the transfer, metabolism and toxic effects of this diverse class of substances, on the human term placenta. [ABSTRACT FROM AUTHOR]

The ex vivo human placenta perfusion model has proven to be clinically relevant to study transfer- and fetal exposure of various drugs. Although the method has existed for a long period, the setup of the perfusion model has not been generalized yet. This review aims to summarize the setups of ex vivo placental perfusion models used to examine drug transfer across the placenta to identify generalized properties and differences across setups. A literature search was carried out in PubMed September 26, 2022. Studies were labeled as relevant when information was reported, between 2000 and 2022, on the setups of ex vivo placental perfusion models used to study drug transfer across the placenta. The placenta perfusion process, and the data extraction, was divided into phases of preparation, control, drug, and experimental reflecting the chronological timeline of the different phases during the entire placental perfusion process. 135 studies describing an ex vivo human placental perfusion experiment were included. Among included studies, the majority (78.5%) analyzed drug perfusion in maternal to fetal direction, 18% evaluated bi-directional drug perfusion, 3% under equilibrium conditions, and one study investigated drug perfusion in fetal to maternal direction. This literature review facilitates the comparison of studies that employ similar placenta perfusion protocols for drug transfer studies and reveals significant disparities in the setup of these ex vivo placental perfusion models. Due to interlaboratory variability, perfusion studies are not readily comparable or interchangeable. Therefore, a stepwise protocol with multiple checkpoints for validating placental perfusion is needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Perfluorinated alkyl acids (PFAAs) are widely used in industry and consumer products. Pregnant women are exposed to PFAAs and their presence in umbilical cord blood represents fetal exposure. Interestingly, PFAAs are substrates for organic anion transporters (OAT) of which OAT4 is expressed in human placenta.Methods: To evaluate the contribution of OAT4 and ATP-binding cassette transporter G2 (ABCG2) proteins in the transplacental transfer of perfluoro octane sulfonate (PFOS) and perfluoro octanoate (PFOA) an ex vivo dual recirculating human placental perfusion was used. Altogether 8 placentas from healthy mothers with uncomplicated pregnancies were successfully perfused.Results: Both PFOS and PFOA crossed the placenta as suggested by in vivo data in the literature. The expression of OAT4 and ABCG2 proteins were studied by immunoblotting and correlation with the transfer index %(TI %) of PFOS and PFOA at 120 and 240 min (n = 4) was studied. The expression of OAT4 was in negative correlation with TI % of PFOA (R(2) = 0.92, p = 0.043) and PFOS (R(2) = 0.99, p = 0.007) at 120 min while at 240 min the correlation was statistically significant only with PFOA. The expression of ABCG2 did not correlate with TI% of PFOS or PFOA.Discussion: Data obtained in this study suggest the involvement of OAT4 in placental passage of PFAAs. Placental passage of PFOS and PFOA is modified by the transporter protein OAT4 but not by ABCG2. This is the first study indicating that OAT4 may decrease the fetal exposure to PFAAs and protect the fetus after maternal exposure to PFAAs but further studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To characterize transplacental transfer of melamine and related mechanisms as well as toxicity using human placental perfusion and cultured cells. Methods: Transfer and toxicity were analyzed in 4-h perfusions with 10 μM or 1 mM melamine, or 10 μM melamine with 10 nM cyanuric acid (CYA). Efflux transporters were studied in accumulation assay and toxicity in BeWo cells by MTT assay. Results: Of added melamine 34–45% was transferred to fetal circulation and CYA made no difference. Histology, hCG production, and PLAP activity indicated functionality of placental tissue with no grave toxicity. Highest concentration of melamine used (2 mM) with CYA and long treatment time decreased viability of BeWo cells. Inhibitors of ABCB1, ABCG2, ABCC2 did not affect the accumulation of melamine in cells. Conclusion: Melamine goes through human term placenta with no contribution of efflux transporters. Toxicity of melamine is low in placental tissue and BeWo cells. [Copyright &y& Elsevier]

Abstract: Nitrosodimethylamine (NDMA) is a carcinogenic compound present in tobacco smoke and food such as cured meat, smoked fish and beer. The O 6-methylguanine formed in human cord blood in mothers highly exposed to such products implicates NDMA exposure of the fetus. Dual recirculating human placental perfusion was used to get direct evidence of the transplacental transfer of NDMA and DNA adduct formation in perfused human placenta. Eleven placentas from normal full-term pregnancies were collected immediately after delivery and an isolated lobule was perfused with 1 or 5μM of 14C-NDMA with a reference substance, antipyrine (0.1mg/ml) added to the maternal circulation. Perfusate samples were collected from both maternal and fetal circulations every half an hour for the first two hours and once per hour from thereon. NDMA was analyzed by scintillation counting and antipyrine by high performance liquid chromatography. The transfer of NDMA was comparable to that of antipyrine and probably occurred through passive diffusion, with the concentrations in maternal and fetal sides equilibrating in 2–3h. No indication of any effect by efflux transporters on NDMA kinetics was noticed in the experiments utilizing Caco-2 or MDCK- MDCKII-MDR1 cell culture monolayer in a transwell system, either. Furthermore, no NDMA-DNA-adducts were found after the perfusions and no DNA-binding of NDMA was seen in in vitro incubations with human placental microsomes from 8 additional placentas. Thus, our study demonstrates that the human fetus can be exposed to NDMA from the maternal circulation. According to this study and the literature, NDMA is not metabolized in full-term human placenta from healthy non-smoking, non-drinking mothers. It remains to be studied whether NDMA concentrations high enough to evoke fetal toxicity can be obtained from dietary sources. [Copyright &y& Elsevier]