Modelling of Human Transplacental Transport as Performed in Copenhagen, Denmark

Abstract

Placenta perfusion models are very effective when studying the placental mechanisms in order to extrapolate to reallife situations. The models are most often used to investigate the transport of substances between mother and foetus, including the potential metabolism of these. We have studied the relationships between maternal and foetal exposures to various compounds including pollutants such as polychlorinated biphenyls, polybrominated flame retardants, nanoparticles as well as recombinant human antibodies. The compounds have been studied in the human placenta perfusion model and to some extent in vitro with an established human monolayer trophoblast cell culture model. Results from our studies distinguish placental transport of substances by physicochemical properties, adsorption to placental tissue, binding to transport and receptor proteins and metabolism. We have collected data from different classes of chemicals and nanoparticles for comparisons across chemical structures as well as different test systems. Our test systems are based on human material to bypass the extrapolation from animal data. By combining data from our two test systems, we are able to rank and compare the transport of different classes of substances according to their transport ability. Ultimately, human data including measurements in cord blood contribute to the study of placental transport.With our work, we contribute to the paradigm shift in toxicology research from the use of animal studies towards alternative models with high relevance to human beings. Modes of actions, exposures and analysis can be studied with modelling, new omics technologies and in silico testing, preferably including study material of human origin [1,2]. Replacement of animal use in this area calls for human mechanistic and human toxicity pathway analysis bridged with exposure information as currently developed in the USA in the report Toxicity Testing in the 21st Century: A Vision and a Strategy [3], which also includes transport studies across cellular barriers such as the placenta.Risks from prenatal exposure to environmental toxicants are highly dependent on placental transport of substances from the maternal circulation to the foetal circulation. The presence of a substance in human cord blood is the ultimate demonstration of transport during pregnancy. Placental transport kinetics can be investigated by using the human dually perfused recirculating placental perfusion model and the BeWo cell transfer model.In the placental perfusion model, a human term placenta is obtained directly after birth and a single cotyledon is reperfused in the laboratory set-up. Foetal and maternal circulations are re-established by a pump system, and the transport of a chosen test substance can be investigated. This perfusion model is a simplified model of placental transport, and it does not take all the physiological and biochemical variables in the mother and foetus into account. The model can only represent transport in the late third trimester. However, the ass...

A perspective on the developmental toxicity of inhaled nanoparticles

“…When systemically available, placental translocation of particles into the fetus has been demonstrated for various types of NP. Data from ex vivo [58,59,67] and in vitro cellular barrier models of the placenta all indicate that placental transport of NP across the placenta, i.e., from the maternal to the fetal compartment is possible [56,57,68,69]. Furthermore, there was good agreement between findings from the in vitro cell system and the human placenta model [69].…”

“…Data from ex vivo [58,59,67] and in vitro cellular barrier models of the placenta all indicate that placental transport of NP across the placenta, i.e., from the maternal to the fetal compartment is possible [56,57,68,69]. Furthermore, there was good agreement between findings from the in vitro cell system and the human placenta model [69]. Animal studies using exposure via IV injection indicate that transplacental passage of NM depends on particle characteristics (size, surface coating), route, dose and duration of exposure, as well as on the animal model and timing in pregnancy.…”

Animal Models of Fetal Medicine and Obstetrics

“…The 3Rs should be considered in all other types of animal experimentation [75], including the options for replacement, which is the first R. One obvious alternative option is to use the placenta from women who have just given birth [76]. The maternal and the fetal circulations are re-established with a pump system, and this option has been used to study the passage of chemical substances from mother to fetus [77]. In addition to the fact that this alternative can replace the use of live animals, it also has the advantage of avoiding problems related to species differences in the maternal-fetal barrier.…”

Workshop of Scandinavian Society for Cell Toxicology 25‐27 September 2013 in Denmark

“…Ex vivo models for studies of placental and skin transport were presented by Lisbeth E. Knudsen and Jesper B. Nielsen [11,12] followed by a number of papers reporting on recent development and application of biomarkers in sensitization [13], neurotoxicity [7] and exposures to dioxin-like activity [14].…”