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The human placenta is a multifunctional organ constituting the barrier between maternal and fetal tissues. Nanoparticles can cross the placental barrier, and there is increasing evidence that the extent of transfer is dependent on particle characteristics and functionalization. While translocated particles may pose risks to the growing fetus particles may also be engineered to enable new particle-based therapies in pregnancy. In both cases, a comprehensive understanding of nanoparticle uptake, accumulation and translocation is indispensable and requires predictive placental transfer models. We examine and evaluate the current literature to draw first conclusions on the possibility to steer translocation of nanoparticles. In addition, we discuss if current placental models are suitable for nanoparticle transfer studies and suggest strategies to improve their predictability.

Although various drugs, environmental pollutants and nanoparticles (NP) can cross the human placental barrier and may harm the developing fetus, knowledge on predictive placental transfer rates and the underlying transport pathways is mostly lacking. Current available in vitro placental transfer models are often inappropriate for translocation studies of macromolecules or NPs and do not consider barrier function of placental endothelial cells (EC). Therefore, we developed a human placental in vitro co-culture transfer model with tight layers of trophoblasts (BeWo b30) and placental microvascular ECs (HPEC-A2) on a low-absorbing, 3 µm porous membrane. Translocation studies with four model substances and two polystyrene (PS) NPs across the individual and co-culture layers revealed that for most of these compounds, the trophoblast and the EC layer both demonstrate similar, but not additive, retention capacity. Only the paracellular marker Na-F was substantially more retained by the BeWo layer. Furthermore, simple shaking, which is often applied to mimic placental perfusion, did not alter translocation kinetics compared to static exposure. In conclusion, we developed a novel placental co-culture model, which provides predictive values for translocation of a broad variety of molecules and NPs and enables valuable mechanistic investigations on cell type-specific placental barrier function.

Background: Epidemiological and animal studies provide compelling indications that environmental and engineered nanomaterials (NMs) pose a risk for pregnancy, fetal development and offspring health later in life. Understanding the origin and mechanisms underlying NM-induced developmental toxicity will be a cornerstone in the protection of sensitive populations and the design of safe and sustainable nanotechnology applications. Main body: Direct toxicity originating from NMs crossing the placental barrier is frequently assumed to be the key pathway in developmental toxicity. However, placental transfer of particles is often highly limited, and evidence is growing that NMs can also indirectly interfere with fetal development. Here, we outline current knowledge on potential indirect mechanisms in developmental toxicity of NMs. Short conclusion: Until now, research on developmental toxicity has mainly focused on the biodistribution and placental translocation of NMs to the fetus to delineate underlying processes. Systematic research addressing NM impact on maternal and placental tissues as potential contributors to mechanistic pathways in developmental toxicity is only slowly gathering momentum. So far, maternal and placental oxidative stress and inflammation, activation of placental toll-like receptors (TLRs), impairment of placental growth and secretion of placental hormones, and vascular factors have been suggested to mediate indirect developmental toxicity of NMs. Therefore, NM effects on maternal and placental tissue function ought to be comprehensively evaluated in addition to placental transfer in the design of future studies of developmental toxicity and risk assessment of NM exposure during pregnancy.

BackgroundGold nanoparticles (AuNPs) are promising candidates to design the next generation NP-based drug formulations specifically treating maternal, fetal or placental complications with reduced side effects. Profound knowledge on AuNP distribution and effects at the human placental barrier in dependence on the particle properties and surface modifications, however, is currently lacking. Moreover, the predictive value of human placental transfer models for NP translocation studies is not yet clearly understood, in particular with regards to differences between static and dynamic exposures. To understand if small (3–4 nm) AuNPs with different surface modifications (PEGylated versus carboxylated) are taken up and cross the human placental barrier, we performed translocation studies in a static human in vitro co-culture placenta model and the dynamic human ex vivo placental perfusion model. The samples were analysed using ICP-MS, laser ablation-ICP-MS and TEM analysis for sensitive, label-free detection of AuNPs.ResultsAfter 24 h of exposure, both AuNP types crossed the human placental barrier in vitro, although in low amounts. Even though cellular uptake was higher for carboxylated AuNPs, translocation was slightly increased for PEGylated AuNPs. After 6 h of perfusion, only PEGylated AuNPs were observed in the fetal circulation and tissue accumulation was similar for both AuNP types. While PEGylated AuNPs were highly stable in the biological media and provided consistent results among the two placenta models, carboxylated AuNPs agglomerated and adhered to the perfusion device, resulting in different cellular doses under static and dynamic exposure conditions.ConclusionsGold nanoparticles cross the human placental barrier in limited amounts and accumulate in placental tissue, depending on their size- and/or surface modification. However, it is challenging to identify the contribution of individual characteristics since they often affect colloidal particle stability, resulting in different biological interaction in particular under static versus dynamic conditions. This study highlights that human ex vivo and in vitro placenta models can provide valuable mechanistic insights on NP uptake and translocation if accounting for NP stability and non-specific interactions with the test system.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0406-6) contains supplementary material, which is available to authorized users.

Safety assessment of the effects of developmental toxicants on pregnant women is challenging, and systemic effects in embryo–maternal interactions are largely unknown. However, most developmental toxicity studies rely on animal trials, while in vitro platforms that recapitulate the maternal–placental–embryonic axis are missing. Here, the development of a dedicated microfluidic device for co‐cultivation of a placental barrier and 3D embryoid bodies to enable systemic toxicity testing at the embryo–maternal interface is reported. The microfluidic platform features simple handling and recuperation of both tissue models, which facilitates post‐hoc in‐depth analysis at the tissue and single‐cell level. Gravity‐driven flow enables inter‐tissue communication through the liquid phase as well as simple and robust operation and renders the platform parallelizable. As a proof of concept and to demonstrate platform use for systemic embryotoxicity testing in vitro, maternal exposure to plastic microparticles is emulated, and microparticle effects on the embryo–placental co‐culture are investigated.

One of the challenges in using in vitro data to understand the potential risks of engineered nanomaterials 22 (ENMs) is that results often differ or are even contradictory among studies. While it is recognized that 23 numerous factors can influence results produced by nanobioassays, there has not yet been a consistently used conceptual framework to identify key sources of variability in these assays. In this paper, we use 25 cause-and-effect analysis to systematically describe sources of variability in four key in vitro 26 nanobioassays: the DCF (2',7'-dichlorofluorescein) assay, an enzyme-linked immunosorbent assay (ELISA) 27 for measuring interleukin-8, a flow cytometry assay (Annexin V/Propidium Iodide), and the Comet assay. 28 These assays measure endpoints that can occur in cells impacted by ENMs through oxidative stress, a 29 principle mechanism for ENM toxicity. The results from this analysis identify control measurements to test 30 for potential artifacts or biases that could occur during conduct of these assays with ENMs. Cause-and-31 effect analysis also reveal additional measurements that could be performed either in preliminary 32 experiments or each time the assay is run to increase confidence in the assay results and their 33 reproducibility within and among laboratories. The approach applied here with these four assays can be 34 used the support the development of a broad range of nanobioassays. 35

Investigating the accumulation and translocation of titanium dioxide nanoparticles with different surface modifications in static and dynamic human placental transfer models. European Journal of Pharmaceutics and Biopharmaceutics, (25 pp.).