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FRIMEDBIO-Fri prosj.st. med.,helse,biol

TeraEpi: Teratogenicity of anti-seizure medication: the roles of epigenetics and folic acid supplements

Alternative title: TeraEpi: Teratogene effekter av legemidler mot epilepsi i svangerskapet - hvilken rolle spiller epigenetikk og folsyretilskudd?

Awarded: NOK 8.2 mill.

Every day thousands of pregnant women worldwide are prescribed medications for which we do not have sufficient information on fetal safety. Pregnant women are not included in randomized clinical trials due to ethical considerations, and medications are being marketed without sufficient information on safety during pregnancy. Epilepsy is a prevalent chronic disease and affects one in 250 pregnant women. Most need daily treatment with at least one anti-seizure medication (ASM) to control seizures. Uncontrolled epilepsy in a pregnant woman is potentially life-threatening for both mother and the unborn child. On the other hand, the use of ASMs during pregnancy can be harmful for the fetus. Thus, the clinician is left with a dilemma when weighing risks against benefits for pregnant women and the unborn child. Although this dilemma has been acknowledged for decades, the underlying mechanisms of the harmful effects of ASMs remain remarkably elusive. The aim of the TeraEpi project is to unravel these mechanisms. One hypothesis is that exposure of the fetus to ASMs leads to changes in epigenetic patterns, i.e., changes in the molecular mechanism for regulating gene expression. Epigenetics is considered a regulator of gene expression, orchestrating both timing and level of gene expression during normal fetal development. We will analyse epigenetic patterns in cord blood samples from the large Norwegian Mother, Father and Child cohort (MoBa). Specifically, we will compare epigenetic patterns in children exposed to ASMs during pregnancy with children who were not exposed. Moreover, we will also investigate the effect of maternal intake of folic acids supplements on epigenetic patterns and its potential preventive effects. Improved understanding of mechanisms of harmful effects of ASMs is a prerequisite for improved follow-up of pregnant women with epilepsy, and for implementation of effective protective measures in the future.

The teratogenicity of anti-seizure medication (ASM) has been acknowledged for decades, but the underlying mechanisms remain remarkably elusive. This gap of knowledge precludes both discovery and development of preventive measures, and improved follow-up and guidelines of pregnant women with epilepsy. Through unravelling underlying mechanisms involved in the teratogenicity of ASM, we aim at improving knowledge and safety of ASM in pregnancy. Specifically, we will investigate if epigenetic mechanisms are involved in the teratogenicity of different ASMs and whether folic acid supplementation modifies this interaction. We will conduct an epigenome-wide association study (EWAS) in cord blood samples from the large Norwegian Mother, Father and Child (MoBa) cohort and apply advanced statistical methods to strengthen causal inference and interpretation. Through integrating genetic and epigenetic (DNA methylation) data the project may elucidate the current knowledge gap between ASM exposure and outcome, by promoting a mechanistic understanding of potential adverse neurodevelopmental outcomes upon ASM exposure. Through access to assessments of verbal development, motor skills, symptoms of autism and ADHD in MoBa, our results can be linked to long-term neurodevelopmental outcomes in the child. Lastly, we will aim at replicating the results in two European birth cohorts. We apply for funding of a PhD and a Post-doc fellow who will be working in an interdisciplinary project group comprising national and international experts in epidemiology, neurology, nutrition, pharmacology, bioinformatics, statistics, genetics and epigenetics. This is a timely and pioneering project, which enters an emerging field in medicine termed pharmacoepigenetics, with the potential to explain how epigenetic variation modulates the drug effects.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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