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General Anesthetics Induce Epigenetic Alterations in Germ Cells that Result in Autism-like Behaviors

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE167500 | GEO | 2021/05/20

REPOSITORIES: GEO

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Project description:Background: DNA methylation (DNAme) erasure and reacquisition occurs during prenatal male germ cell development; some further remodelling takes place after birth during spermatogenesis. Environmental insults during germline epigenetic reprogramming may affect DNAme, presenting a potential mechanism for transmission of environmental exposures across multiple generations. Objectives: We investigated how germ cell DNAme is impacted by lifetime exposures to diets containing either low or high, clinically relevant, levels of the methyl donor folic acid and whether resulting DNAme alterations were inherited in germ cells of male offspring of subsequent generations. Materials and Methods: Female mice were placed on a 7-fold folic acid deficient (7FD) and 10- or 20-fold supplemented (10FS and 20FS) diets before and during pregnancy. Resulting F1 litters were weaned on the respective diets. F2 and F3 males received control diets. Genome-wide DNAme was assessed in F1 spermatogonia, and in F1, F2 and F3 sperm. Results: In F1 germ cells, a greater number of differentially methylated cytosines (DMCs) was observed in spermatogonia as compared with F1 sperm for all folic acid diets. DMCs were lower in number in F2 versus F1 sperm, while an unexpected increase was found in F3 sperm. DMCs were predominantly hypomethylated, with genes in neurodevelopmental pathways commonly affected in F1, F2 and F3 male germ cells. While no DMCs were found to be inherited inter- or transgenerationally, we observed over-representation of repetitive elements, particularly young LINEs. Discussion and Conclusion: These results suggest that the prenatal window is the time most susceptible to folate-induced alterations in sperm DNAme in male germ cells. Altered methylation of specific sites in F1 sperm was not present in later generations. However, the finding of hypomethylated young LINE1 elements in sperm from F1 to F3 males provides insight into potential mechanisms of epigenetic inheritance of the effects of folate deficiency and supplementation.

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General Anesthetics Induce Epigenetic Alterations in Germ Cells that Result in Autism-like Behaviors

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