The placental barrier and the fetal exposome: exploring the mechanisms underlying fetal exposures
Lead Research Organisation:
University of Southampton
Department Name: Human Development and Health
Abstract
Over 80% of pregnant women need to take medicines for their health. Medication is often essential to treat serious medical conditions such as diabetes, depression, infections, and multiple sclerosis. While the baby is growing in the womb, it is partially protected from drugs and environmental toxins in the mother's blood by an organ called the placenta (also known as the afterbirth). Many medicines cross the placenta (e.g. the antidiabetic drug metformin), but it is not always clear how this happens. It is not just medicines that may cross the placenta. Pregnant women encounter many potentially harmful compounds in their environment that they cannot easily avoid. These include nanoparticles from diesel, plastic, or even home cooking, heavy metals (e.g. lead in paint), food additives and workplace exposures.
The placenta has a difficult job as it must protect the baby from harmful drugs and toxins in the maternal blood while also feeding the baby in the womb. The protective barrier within the placenta is called the syncytiotrophoblast. If the placental syncytiotrophoblast does not work effectively, the baby may be exposed to drugs, toxins or viruses that stop it from developing as it should. These developmental problems could lead to birth defects or more subtle problems that increase the risk of chronic diseases later in life.
Because pregnant women may be exposed to a wide range of chemicals, we need to understand which types of chemicals cross the placenta most effectively. The substances that cross the placenta most easily may be more dangerous to the baby in the womb. This study is unique in that it will study the transfer of many substances at once. To do this, we will use a technique called nuclear magnetic resonance, which can measure the levels of multiple chemicals in the same samples. This will reduce the number of experiments we need to do tenfold, meaning we get the data faster and cost-effectively.
We have used new microscopes to discover tiny (nanoscale) structures in the placenta. Using these microscopes, we have recently shown that the syncytiotrophoblast is punctuated by tiny holes that span the entire thickness of the barrier. We have called these holes called trans-syncytial nanopores. These holes can be 2000 times thinner than a human hair but are big enough for many medicines and environmental toxins to pass through. Our new finding that there are many tiny nanopores penetrating the placenta changes the way we think about the placenta barrier, from a solid wall between the mother and the fetus to something more like a fine sieve.
Nanopores may be necessary to help regulate how the baby grows and develops in the womb. We think nanopores may ensure that the baby gets the right balance of water and salts. The right balance of water and salts allows the baby to grow correctly. However, in performing these useful roles, the nanopores may also allow harmful chemicals to reach the fetus.
Once we have a better understanding of the nanopores, future studies will be able to assess their impact on fetal health. These impacts may be positive, e.g. balancing water and salts, or harmful, e.g. exposing the baby to helpful or toxic substances. This study will help doctors to decide which medicines are safe and environmental agencies to understand what forms of pollution are the greatest risk to pregnant women. Although nanopores may expose the baby to dangerous chemicals, they could also allow good things across the placenta to the baby, for instance, medicines or nutrients the baby needs. Using the knowledge this project will generate, scientists could design medicines more likely to travel through the nanopores and reach the fetus. Babies born healthy are more likely to be healthy later in life, which has personal, social and economic benefits.
The placenta has a difficult job as it must protect the baby from harmful drugs and toxins in the maternal blood while also feeding the baby in the womb. The protective barrier within the placenta is called the syncytiotrophoblast. If the placental syncytiotrophoblast does not work effectively, the baby may be exposed to drugs, toxins or viruses that stop it from developing as it should. These developmental problems could lead to birth defects or more subtle problems that increase the risk of chronic diseases later in life.
Because pregnant women may be exposed to a wide range of chemicals, we need to understand which types of chemicals cross the placenta most effectively. The substances that cross the placenta most easily may be more dangerous to the baby in the womb. This study is unique in that it will study the transfer of many substances at once. To do this, we will use a technique called nuclear magnetic resonance, which can measure the levels of multiple chemicals in the same samples. This will reduce the number of experiments we need to do tenfold, meaning we get the data faster and cost-effectively.
We have used new microscopes to discover tiny (nanoscale) structures in the placenta. Using these microscopes, we have recently shown that the syncytiotrophoblast is punctuated by tiny holes that span the entire thickness of the barrier. We have called these holes called trans-syncytial nanopores. These holes can be 2000 times thinner than a human hair but are big enough for many medicines and environmental toxins to pass through. Our new finding that there are many tiny nanopores penetrating the placenta changes the way we think about the placenta barrier, from a solid wall between the mother and the fetus to something more like a fine sieve.
Nanopores may be necessary to help regulate how the baby grows and develops in the womb. We think nanopores may ensure that the baby gets the right balance of water and salts. The right balance of water and salts allows the baby to grow correctly. However, in performing these useful roles, the nanopores may also allow harmful chemicals to reach the fetus.
Once we have a better understanding of the nanopores, future studies will be able to assess their impact on fetal health. These impacts may be positive, e.g. balancing water and salts, or harmful, e.g. exposing the baby to helpful or toxic substances. This study will help doctors to decide which medicines are safe and environmental agencies to understand what forms of pollution are the greatest risk to pregnant women. Although nanopores may expose the baby to dangerous chemicals, they could also allow good things across the placenta to the baby, for instance, medicines or nutrients the baby needs. Using the knowledge this project will generate, scientists could design medicines more likely to travel through the nanopores and reach the fetus. Babies born healthy are more likely to be healthy later in life, which has personal, social and economic benefits.
Technical Summary
Fetal exposure to xenobiotics such as pharmaceuticals and environmental exposures can cause congenital disabilities, restrict fetal growth and impair the physiological resilience required for healthy ageing. Fetal exposure to environmental toxins, drugs & their maternal metabolites, and nanoparticles are mediated by the placenta.
The syncytiotrophoblast was thought to be a continuous barrier to diffusion across the placenta. However, we now show that trans-syncytial nanopores provide a water-filled pathway for the simple diffusion of hydrophilic compounds. This discovery changes how we conceive of the placental barrier. As such, assessing the relative roles of diffusion and membrane transport in the placental barrier in normal pregnancy is timely. Understanding the permeability of the nanopores is now crucial for biologists, pharmacologists, food technologists and environmental scientists.
Placental transfer via diffusion and membrane transport proteins will be investigated using a cocktail of hydrophilic pharmaceutical and environmental toxins in the isolated perfused human placenta. Diffusive and transporter-mediated transfer will be quantified under specific experimental conditions, and computational modelling will be used to separate these components. The models can then be used to predict transport across the placenta.
The project will establish the transport capacity of the nanopores and, using mathematical modelling, assess the relative importance of diffusion through nanopores and transporter mediate routes for a range of chemicals. Super-resolution light microscopy will be used to explore the mechanisms of nanopore formation and provide insight into their physiological role.
The syncytiotrophoblast was thought to be a continuous barrier to diffusion across the placenta. However, we now show that trans-syncytial nanopores provide a water-filled pathway for the simple diffusion of hydrophilic compounds. This discovery changes how we conceive of the placental barrier. As such, assessing the relative roles of diffusion and membrane transport in the placental barrier in normal pregnancy is timely. Understanding the permeability of the nanopores is now crucial for biologists, pharmacologists, food technologists and environmental scientists.
Placental transfer via diffusion and membrane transport proteins will be investigated using a cocktail of hydrophilic pharmaceutical and environmental toxins in the isolated perfused human placenta. Diffusive and transporter-mediated transfer will be quantified under specific experimental conditions, and computational modelling will be used to separate these components. The models can then be used to predict transport across the placenta.
The project will establish the transport capacity of the nanopores and, using mathematical modelling, assess the relative importance of diffusion through nanopores and transporter mediate routes for a range of chemicals. Super-resolution light microscopy will be used to explore the mechanisms of nanopore formation and provide insight into their physiological role.
