Computational modelling to evaluate, understand and predict the placental transfer of xenobiotics as an integrated system

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During pregnancy the baby in the womb can be exposed to medicines the mother is taking and other poisonous substances she might be exposed to. These drugs and poisons are transferred from the mother to the baby via the placenta, which is the organ that connects the baby in the womb to the mother via the umbilical cord. There is currently a lot of uncertainty around exactly how certain substances cross the placenta and to what extent. This lack of information has resulted in pregnant mothers taking drugs that are potentially unsafe, or in contrast led to the advice to avoid drugs required to make the mother better when that was in fact not necessary. To address these issues it is essential that we understand better how the placenta works. Placental transfer is very complex, therefore in this project we propose to use computer simulations to understand better how substances such as drugs and poisonous substances cross the placenta.Within the placenta the blood from the mother and the baby's blood coming from the umbilical cord do not mix, instead they are kept separated by particular barrier membranes. These placental membranes contain specific transporter molecules that can take certain substances across (for example nutrients needed by the baby), while excluding others. Transporters can also play an active role, allowing the placenta to protect the fetus by pumping out harmful substances. Although we understand how transport proteins work in isolation, we now need to understand how they all work together, and that is where our computer simulations are needed.We will use laboratory experiments in which placental cells are grown on a porous filter to form a barrier layer. We will then do experiments with lots of different situations to see how much is being transferred across the membranes and then use our computer simulations to work out what all the membrane transporters were doing. We will then compare these results with those from the so called 'placenta-on-a-chip', which is a little laboratory system in which we mimic the effect of the blood flow in the placenta.Finally we will take real placentas (donated after birth) into the laboratory and connect them up with pumps on both the maternal and fetal side. This will allow us to study the transfer of medicines without endangering the baby. We can then test precisely if our computer simulations can accurately predict what is going on in the real placenta. By combining computer simulations and experiments in this way we will be able to understand better how the placenta works and to what extent drugs and poisonous substances go across from the mother to the baby in the womb.