GSE167500
General Anesthetics Induce Epigenetic Alterations in Germ Cells that Result in Autism-like Behaviors
One in 54 children in the U.S. is diagnosed with Autism Spectrum Disorder (ASD). However, no one genetic mutation can fully explain the neuropathogenesis of ASD. Given the highly heritable nature of ASD, epigenetic alterations may be the missing link in understanding ASD. Human and animal studies have shown that exposure of the developing brain to anesthetic agents can trigger neurodegeneration and neurobehavioral abnormalities but the effect of general anesthetics on the germ line have not been explored in detail. The gametes carry inherited epigenetic information and they are extremely vulnerable to environmental factors when they undergo epigenetic reprogramming in utero. To understand the inheritable impact of general anesthetics, we exposed pregnant mice to sevoflurane when the germ cells of the embryo undergo epigenetic reprogramming and examined the exposed males and their offspring. We found that 30-40% of the F2 and F3 animals, which were not directly exposed to sevoflurane, exhibit ASD-like behaviors. We performed ATAC-seq in the sperm of F1 animals that give rise to the autistic F2 animals and in sperm of the autistic F2 animals, and found more than 2,000 differential accessible sites. Some of these sites are maintained in the sperm of F2 and F3 animals and are located in the regulatory regions of ASD-associated genes, including Cacna1e and Arid1b. These observations suggest that epimutations caused by exposing germ cells to general anesthetics can lead to ASD in the offspring, and this effect can be transmitted through the male germline inter and trans-generationally. Overall design: Identifying sevoflurance induced alteration of transcription factors in sperm