The placental barrier and the fetal exposome: exploring the mechanisms underlying fetal exposures

超过80%的孕妇需要服用药物来保护自己的健康。治疗严重的疾病，如糖尿病、抑郁症、感染和多发性硬化症，药物治疗往往是必不可少的。虽然婴儿在子宫中成长，但通过一个名为胎盘(也称为胎盘)的器官，可以部分保护婴儿免受母亲血液中药物和环境毒素的影响。许多药物穿过胎盘(例如抗糖尿病药物二甲双胍)，但并不总是清楚这是如何发生的。可能跨越胎盘的不仅仅是药物。孕妇在她们的环境中会遇到许多她们无法轻易避免的潜在有害化合物。这些包括来自柴油、塑料甚至家庭烹饪的纳米颗粒、重金属(例如油漆中的铅)、食品添加剂和工作场所暴露。胎盘的工作很困难，因为它必须保护婴儿免受母亲血液中的有害药物和毒素的影响，同时还必须喂养子宫中的婴儿。胎盘内的保护性屏障称为合体滋养层细胞。如果胎盘合体滋养层细胞不能有效工作，婴儿可能会接触到阻止其正常发育的药物、毒素或病毒。这些发育问题可能会导致出生缺陷或更微妙的问题，从而增加日后患慢性病的风险。由于孕妇可能接触到广泛的化学物质，我们需要了解哪些类型的化学物质最有效地穿过胎盘。最容易穿过胎盘的物质可能对子宫中的婴儿更危险。这项研究的独特之处在于它将同时研究许多物质的转移。为了做到这一点，我们将使用一种名为核磁共振的技术，它可以测量同一样本中多种化学物质的水平。这将把我们需要做的实验次数减少到原来的十分之一，这意味着我们获得数据的速度更快，成本效益更高。我们使用了新的显微镜来发现胎盘中的微小(纳米级)结构。使用这些显微镜，我们最近展示了合体滋养层细胞被跨越整个屏障厚度的微孔所点缀。我们称这些孔为跨合胞纳米孔。这些洞可以比人的头发细2000倍，但足够大，可以让许多药物和环境毒素通过。我们的新发现是，有许多微小的纳米孔穿透胎盘，这改变了我们对胎盘屏障的看法，从母亲和胎儿之间的一堵坚固的墙变成了更像一个细筛子的东西。纳米孔可能是必要的，以帮助调节婴儿在子宫中的生长发育。我们认为，纳米孔可以确保婴儿获得适当的水和盐的平衡。适当的水和盐的平衡可以让婴儿正常成长。然而，在发挥这些有用的作用时，纳米孔也可能允许有害化学物质到达胎儿。一旦我们对纳米孔有了更好的了解，未来的研究将能够评估它们对胎儿健康的影响。这些影响可能是积极的，例如平衡水和盐，也可能是有害的，例如使婴儿接触到有益或有毒的物质。这项研究将帮助医生决定哪些药物是安全的，并帮助环境机构了解哪些形式的污染对孕妇的风险最大。虽然纳米孔可能会使婴儿接触到危险的化学物质，但它们也可以通过胎盘向婴儿提供有益的东西，例如婴儿需要的药物或营养物质。利用这个项目将产生的知识，科学家们可以设计出更有可能通过纳米孔到达胎儿的药物。出生健康的婴儿在晚年更有可能健康，这对个人、社会和经济都有好处。

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.