Epitranscriptomic Analysis of N6-methyladenosine in Infant Rhesus Macaques after Multiple Sevoflurane Anesthesia

Abstract

Clinical investigations to date have proposed the possibility that exposure to anesthetics is associated with neurodevelopmental deficits. Sevoflurane is the most commonly used general anesthetic in pediatric patients. Animal studies have demonstrated that multiple exposures to sevoflurane during the postnatal period resulted in neuropathological brain changes and long-term cognitive deficits. However, the underlying mechanisms remain to be clarified. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) was performed to acquire genome-wide profiling of RNA N6-methyladenosine (m6A) in the prefrontal cortex of infant rhesus macaques. The macaques in the sevoflurane group had more m6A peaks than the macaques in the control group (p ≤ 0.05). After sevoflurane treatment, the mRNA levels of YT521-B homology domain family 1 (YTHDF1) and YT521-B homology domain family 3 (YTHDF3) were decreased, and sevoflurane anesthesia dynamically regulated RNA m6A methylation. Gene ontology (GO) analysis revealed that after sevoflurane exposure, genes with increased methylation of m6A sites were enriched in some physiological processes relevant to neurodevelopment, mainly focused on synaptic plasticity. The female macaques had 18 hypermethylated genes. The males had 35 hypermethylated genes, and some physiological processes related to the regulation of synaptic structure were enriched. Rhesus macaques are genetically closer to human beings. Our findings can help in the study of the mechanism of sevoflurane-relevant neurodevelopmental deficits at the posttranscriptional level and can provide new insights into potential clinical preventions and interventions for the neurotoxicity of neonatal anesthesia exposure.