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

胎盘屏障和胎儿暴露组：探索胎儿暴露的机制

• 批准号: BB/X01603X/1
• 负责人: Rohan Lewis
• 金额: $ 64.81万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX01603X%2F1
• 关键词: placental; barrier; fetal; exposome; exploring

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.

超过80%的孕妇需要服用药物来维持健康。药物治疗对于治疗严重的疾病如糖尿病、抑郁症、感染和多发性硬化症通常是必不可少的。当婴儿在子宫中生长时，它被一种称为胎盘（也称为胞膜）的器官部分保护免受母亲血液中的药物和环境毒素的影响。许多药物（例如抗糖尿病药物二甲双胍）可以穿过胎盘，但这是如何发生的并不总是清楚。不仅仅是药物可以穿过胎盘。孕妇在环境中遇到许多潜在的有害化合物，她们无法轻易避免。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体血液中有害药物和毒素的伤害，同时还要喂养子宫内的婴儿。胎盘内的保护屏障称为合体滋养层。如果胎盘合胞体滋养层不能有效地工作，婴儿可能会接触药物，毒素或病毒，阻止其正常发育。这些发育问题可能导致出生缺陷或更微妙的问题，增加以后患慢性疾病的风险。由于孕妇可能接触到各种化学物质，我们需要了解哪种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内的婴儿更危险。这项研究的独特之处在于它将同时研究许多物质的转移。为此，我们将使用一种称为核磁共振的技术，该技术可以测量同一样品中多种化学物质的水平。这将使我们需要做的实验数量减少十倍，这意味着我们可以更快、更经济地获得数据。我们使用新的显微镜来发现胎盘中的微小（纳米级）结构。利用这些显微镜，我们最近发现合体滋养层被跨越整个屏障厚度的小孔所打断。我们将这些孔称为跨合胞体纳米孔。这些小孔比人的头发细2000倍，但足够大，许多药物和环境毒素可以通过。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固体壁变成了更像细筛的东西。纳米孔可能是帮助调节婴儿在子宫内生长发育所必需的。我们认为纳米孔可以确保婴儿获得正确的水和盐的平衡。正确的水和盐的平衡可以让宝宝正确地成长。然而，在执行这些有用的角色时，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，例如使婴儿接触有益或有毒物质。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什么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危险的化学物质，但它们也可以让好东西穿过胎盘到达婴儿，例如婴儿需要的药物或营养素。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。出生时健康的婴儿更有可能在以后的生活中保持健康，这对个人，社会和经济都有好处。