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

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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.