Testicular Histone Hyperacetylation in Mice by Valproic Acid Administration Affects the Next Generation by Changes in Sperm DNA Methylation

Various reports have described epigenetic transgenerational inheritance through sperm. However, the detailed mechanism remains unclear. In this study, we focused on DNA methylation and analyzed the effects on the next generation of sperm from mice treated with valproic acid (VPA) as an inducer of epigenomic changes. Administration of 200 mg/kg/day VPA to mice for 4 weeks caused transient histone hyperacetylation in the testes and DNA methylation changes in sperm, including promoter CpGs of genes related to brain function. Oocytes fertilized by VPA-treated mouse sperm showed some methylation fluctuations at the morula stage. Pups fathered by these mice also showed behavioral changes in the light/dark transition test after maturation. Brain RNA-seq of these mice showed decreased expression of many genes related to brain and neural function. Comparison of the sperm DNA methylation status of the next generation of mice with that of the parental generation revealed the disappearance of the methylation changes observed in the sperm of the parental generation. These findings suggest that VPA-treated mice may be a useful simple epigenetic transgenerational inheritance model for histone hyperacetylation.