Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Joëlle Rüegg, Uppsala University, Sweden
- Second opponent: Researcher Robert Illingworth, University of Edinburgh, Scotland
- Third member and chair of the evaluation committee: Associate Professor Camila Vicencio Esguerra, University of Oslo
Chair of the Defence
Professor Bjørn Steen Skålhegg, University of Oslo
Principal Supervisor
Group Leader Robert Lyle, Oslo University Hospital
Summary
Medications taken during pregnancy may reach the developing fetus and interfere with neurodevelopmental processes, and possibly increase the risk of disease in later life. Epigenetic modifications have been proposed as a mechanism linking medication exposure to adverse neurodevelopmental outcomes. This thesis examines the effect of paracetamol and citalopram on epigenetic and gene expression patterns during neuronal differentiation of human embryonic stem cells.
The thesis presents an in vitro neuronal differentiation protocol of human embryonic stem cells optimised for neuropharmacological applications. A molecular timeline of gene expression and epigenetic patterns at four timepoints during neuronal differentiation was developed. Next, the neuronal differentiation model was employed to study the effect of paracetamol exposure at therapeutic concentrations. Paracetamol induced changes in gene expression, DNA methylation and chromatin accessibility in genes important for brain development and function, as well as for genes implicated in neurodevelopmental disorders, indicating possible paracetamol-mediated mechanisms. An overlap was found with changes in DNA methylation in the cord blood of children with ADHD exposed to paracetamol during pregnancy.
Exposure to therapeutic concentrations of citalopram demonstrated time- and dose-dependent effects on gene expression associated with brain functions and depression, but not DNA methylation, suggesting the involvement of alternative gene regulatory mechanisms.
This research provides insights into how medications used by pregnant women can impact fetal brain development. This is crucial knowledge for better understanding the mechanisms, safety, and long-term effects of medication use during pregnancy.
Additional information
Contact the research support staff.