Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol
Mari Spildrejorde,
Athina Samara,
Ankush Sharma,
Magnus Leithaug,
Martin Falck,
Stefania Modafferi,
Arvind Y.M. Sundaram,
Ganesh Acharya,
Hedvig Nordeng,
Ragnhild Eskeland,
Kristina Gervin,
Robert Lyle
Affiliations
Mari Spildrejorde
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Athina Samara
Division of Clinical Paediatrics, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children′s Hospital, Karolinska University Hospital, Stockholm, Sweden; Corresponding author
Ankush Sharma
Department of Informatics, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway
Magnus Leithaug
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
Martin Falck
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; Department of Biosciences, University of Oslo, Oslo, Norway
Stefania Modafferi
Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
Arvind Y.M. Sundaram
Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway
Ganesh Acharya
Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Alfred Nobels Allé 8, SE-14152 Stockholm, Sweden; Center for Fetal Medicine, Karolinska University Hospital, SE-14186 Stockholm, Sweden
Hedvig Nordeng
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, University of Oslo, Oslo, Norway
Ragnhild Eskeland
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; Corresponding author
Kristina Gervin
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, University of Oslo, Oslo, Norway; Division of Clinical Neuroscience, Department of Research and Innovation, Oslo University Hospital, Oslo, Norway
Robert Lyle
PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway; Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
Summary: Prenatal paracetamol exposure has been associated with neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies show differences in cord blood DNA methylation between unexposed and paracetamol-exposed neonates, however, causality and impact of long-term prenatal paracetamol exposure on brain development remain unclear. Using a multi-omics approach, we investigated the effects of paracetamol on an in vitro model of early human neurodevelopment. We exposed human embryonic stem cells undergoing neuronal differentiation with paracetamol concentrations corresponding to maternal therapeutic doses. Single-cell RNA-seq and ATAC-seq integration identified paracetamol-induced chromatin opening changes linked to gene expression. Differentially methylated and/or expressed genes were involved in neurotransmission and cell fate determination trajectories. Some genes involved in neuronal injury and development-specific pathways, such as KCNE3, overlapped with differentially methylated genes previously identified in cord blood associated with prenatal paracetamol exposure. Our data suggest that paracetamol may play a causal role in impaired neurodevelopment.
