Mechanisms via which the human fetus is at risk from over-the-counter analgesics

处方药的使用很普遍，%的美国妇女在怀孕期间开了一种或一种以上的药物(不包括维生素/矿物质)。此外，非处方药的使用非常普遍，特别是用于止痛药(如扑热息痛、布洛芬)。这些药物的使用(包括剂量和频率)很难控制，怀孕期间使用镇痛剂与增加后代先天性缺陷的风险之间存在关联。一个例子是，如果在子宫内(在子宫内)暴露于扑热息痛，新生儿隐睾症的增加和男性化程度的降低。与非妊娠妇女相比，妊娠期间药物的药代动力学发生了很大的变化，对胎儿的代谢、生物转化和药物清除的了解也非常有限。因此，在怀孕期间不适当地接触药物可能会对后代的健康和幸福产生严重的不良影响，这种模式是众所周知的，例如母亲吸烟或大量饮酒。虽然我们和其他人已经证明胎儿的肝脏在妊娠早期/中期活跃，但对涉及药物及其代谢物的摄取、代谢/生物转化和清除的细胞机制知之甚少。因此，该博士学位的目的是确定调节或保护人体胎儿暴露于扑热息痛等镇痛剂及其代谢物带来的潜在风险的肝脏(肝脏)机制。为了实现这一目标，该学生将参与由Fowler协调的SAFER研究(苏格兰高级胚胎研究)。这项研究涉及在阿伯丁和格拉斯哥大学收集和研究选择性终止的正常人类胎儿(怀孕7至20周)(伦理批准：REC：15/NS/0123)。此外，我们(米切尔)已经在一些安全的研究胎儿的血浆中测量到高水平的扑热息痛，清楚地表明这种药物是从母亲进入胎儿的。目标1：学生将对下一代测序(RNA-SEQ)和来自80个胎儿肝脏的蛋白质组数据进行数据挖掘，这些数据已经作为MRC资助给Fowler的一部分获得。这将揭示人类胎儿肝脏参与药物代谢和清除的基因和蛋白质途径，以及是否根据胎儿性别的不同而存在差异。目的2：在爱丁堡，学生将利用Hay的体外肝脏系统来探索镇痛剂及其代谢物对肝功能的影响，以了解与成人和胎儿比较的镇痛剂及其代谢物代谢过程中涉及的细胞内机制。本博士论文的目的是提供对常见非处方药对人胎肝影响的基本机制的理解，以及有关胎儿肝脏对这些镇痛剂及其代谢物的反应的信息。从长远来看，这些数据将有助于设计可供孕妇使用的止痛药，而不会对发育中的胎儿构成严重风险。

The use of prescription medicines is widespread with 64% of USA women prescribed one or more drugs (excluding vitamins/minerals) during pregnancy. Furthermore, use of over-the-counter medicines is very widespread especially for analgesic use (eg paracetamol, ibuprofen). The use (including dose and frequency) of these drugs is difficult to regulate and there are associations between use of analgesics during pregnancy and increased risk of congenital defects in offspring. An example is the increased cryptorchidism and reduced masculinisation of new-born boy infants if they were exposed in-utero (in the womb) to paracetamol. During pregnancy pharmacokinetics of drugs are widely known to be altered compared to non-pregnant women and what is known about fetal human metabolism, biotransformation and clearance of drugs is very limited. Therefore, inappropriate exposure to medicines during pregnancy can have serious adverse effects on the health and wellbeing of the offspring throughout life, a model that is well understood with maternal cigarette smoking or heavy alcohol consumption for instance.While the fetal human liver has been shown by us and others to be active in the late first/second trimester very little is known about the cellular mechanisms involved in uptake, metabolism/biotransformation and clearance of medicines and their metabolites. The aim of this PhD, therefore, is to define the hepatic (liver) mechanisms that mediate, or protect from, the potential risks posed by exposure to analgesics like paracetamol, and their metabolites in the human fetus.In order to achieve this aim, the student will be part of the SAFeR study (Scottish Advanced Fetal Research study) coordinated by Fowler. This study involves the collection and study of electively terminated normal human fetuses (between 7 and 20 weeks of gestation) at the Universities of Aberdeen & Glasgow (ethical approval: REC:15/NS/0123). In addition, we (Mitchell) have already measured high levels of paracetamol in the plasma of some of these SAFeR study fetuses, clearly demonstrating that this medication gets into the fetus from the mother. OBJECTIVE 1: The student will perform data-mining on Next Generation sequencing (RNA-seq) and proteomic data from 80 fetal livers already obtained as part of an MRC grant to Fowler. This will reveal human fetal hepatic gene and protein pathways involved in the metabolism and clearance of medications such as paracetamol and whether there are differences according to fetal sex.OBJECTIVE 2: In Edinburgh the student will utilise Hay's in-vitro liver systems to probe the effects of analgesics and their metabolites on hepatic function to understand the intracellular mechanisms involved in the metabolic processing of analgesics and their metabolites comparing adult with fetal.OBJECTIVE 3: The student will utilise the data from the first two objectives to study livers from fetuses with high and low paracetamol levels in order to determine which hepatic mechanisms offer protective and risk-increasing outcomes for the fetus.The intended impact of this PhD is to provide the basic mechanistic understanding of the effects of common over-the-counter analgesics on the human fetal liver, as well as information on the responses of the fetal liver to those analgesics and their metabolites. In the longer-term such data would be useful in designing analgesics that could be used by pregnant women without posing serious risks to the developing fetus.