权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

人类胎儿面临非处方镇痛药风险的机制

基本信息

批准号：
1942576
负责人：
金额：
--
依托单位：
University of Aberdeen
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1942576
关键词：
Mechanisms via human fetus risk

项目摘要

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.

处方药的使用很普遍，64% 的美国女性在怀孕期间服用一种或多种药物（不包括维生素/矿物质）。此外，非处方药的使用非常普遍，尤其是镇痛药（例如扑热息痛、布洛芬）。这些药物的使用（包括剂量和频率）很难调节，并且怀孕期间使用镇痛药与后代先天性缺陷风险增加之间存在关联。一个例子是，如果新生男婴在子宫内（子宫内）接触扑热息痛，隐睾会增加，男性化会减少。众所周知，与非孕妇相比，怀孕期间药物的药代动力学会发生变化，而对胎儿人体代谢、生物转化和药物清除的了解非常有限。因此，怀孕期间不适当地接触药物可能会对后代一生的健康和福祉产生严重的不利影响，例如，母亲吸烟或大量饮酒就可以很好地理解这一模型。虽然我们和其他人已经证明胎儿肝脏在妊娠早期/中期阶段很活跃，但对于药物的吸收、代谢/生物转化和清除所涉及的细胞机制却知之甚少。药物及其代谢物。因此，该博士的目的是确定肝脏机制，以调节或防止人类胎儿接触扑热息痛等镇痛药及其代谢物所带来的潜在风险。为了实现这一目标，该学生将参加福勒协调的 SAFeR 研究（苏格兰高级胎儿研究）。本研究涉及在阿伯丁大学和格拉斯哥大学选择性终止的正常人类胎儿（妊娠 7 至 20 周）的收集和研究（伦理批准：REC:15/NS/0123）。此外，我们（米切尔）已经在一些 SAFeR 研究胎儿的血浆中测量到了高浓度的扑热息痛，清楚地表明这种药物是从母亲进入胎儿体内的。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，这些数据是作为 MRC 向 Fowler 拨款的一部分而获得的。这将揭示人类胎儿肝脏基因和蛋白质途径参与药物（如扑热息痛）的代谢和清除，以及是否存在根据胎儿性别的差异。目标 2：在爱丁堡，学生将利用 Hay 的体外肝脏系统探讨镇痛药及其代谢物对肝功能的影响，以了解镇痛药和代谢物代谢过程中涉及的细胞内机制。比较成人和胎儿的代谢物。目标 3：学生将利用前两个目标的数据来研究对乙酰氨基酚水平高和低的胎儿的肝脏，以确定哪些肝脏机制为胎儿提供保护和增加风险的结果。本博士学位的预期影响是提供对常见非处方镇痛药对人类胎儿肝脏影响的基本机制理解，以及有关胎儿肝脏对这些镇痛药及其代谢物的反应。从长远来看，这些数据将有助于设计孕妇可以使用的止痛药，而不会对发育中的胎儿造成严重风险。