Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD

Epidemiological studies have shown that long-term exposure to paracetamol during pregnancy is associated with attention-deficit/hyperactivity disorder (ADHD). The mechanism by which paracetamol may modulate the increased risk... [ view full abstract ]

Epidemiological studies have shown that long-term exposure to paracetamol during pregnancy is associated with attention-deficit/hyperactivity disorder (ADHD). The mechanism by which paracetamol may modulate the increased risk of developing ADHD is currently unknown. We have conducted an epigenome-wide association study and investigated whether prenatal exposure to paracetamol is associated with DNA methylation changes, and if such changes were associated with ADHD. The participants (n=384) were selected from a large prospective birth cohort (Norwegian Mother and Child Cohort Study, MoBa), which contains information about medication use during pregnancy. The ADHD diagnoses were obtained from the Norwegian Patient Registry.

           Stratified analyses on ADHD and paracetamol separately did not identify any differentially methylation. However, comparison of samples with ADHD exposed to paracetamol for more than 20 days to healthy controls identified differentially methylated CpGs (n=6 211). In addition, these samples were differentially methylated compared to samples with ADHD exposed to paracetamol for less than 20 days (n=2 089 CpGs) and not exposed to paracetamol (n=193 CpGs). Interestingly, several of the top genes ranked according to significance and effect size have been linked to ADHD, neural development and neurotransmission. Gene ontology analysis revealed enrichment of pathways involved in oxidative stress, neurological processes and the olfactory sensory system, which have previously been implicated in the etiology of ADHD. These initial findings require replication, but suggest a possible mechanism by which prenatal long-term exposure to paracetamol modifies the risk of developing ADHD. Further, these results lend novel insights into the etiology of ADHD and may serve as disease biomarkers in blood.