Multi-omics analysis of paracetamol exposure identifies dysregulated genes involved in neurotoxicity and neuronal differentiation of human embryonic stem cells
Prenatal paracetamol exposure has been associated with neurodevelopmental outcomes in childhood. Pharmacoepigenetic studies show differences in cord blood DNA methylation between paracetamol exposed and unexposed neonates. However, causal implications and impact of long-term prenatal long-term paracetamol exposure on brain development remain unclear. Using a multi-omics approach, we investigated the effects of paracetamol on a model of early human brain development. We exposed human embryonic stem cells undergoing in vitro neuronal differentiation to daily media changes 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 signalling, 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. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/519620v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@e1a75forg.highwire.dtl.DTLVardef@b36a1forg.highwire.dtl.DTLVardef@fc25e4org.highwire.dtl.DTLVardef@1bb1c8_HPS_FORMAT_FIGEXP M_FIG C_FIG