Paternal Folic Acid Supplementation Alleviated Hepatic Steatosis in Male Offspring Through Sperm DNA Methylation Modification

ABSTRACT In recent years, studies have demonstrated a link between paternal preconception nutrient exposure and the phenotype of the offspring. However, there is a paucity of direct scientific evidence on the effects and the underlying mechanism of paternal folic acid supplementation (PFAS) on offspring phenotype. In this study, male mice were fed different doses of folic acid for 10 weeks, and then mated with females to produce offspring. In our findings, male offspring of PFAS fathers exhibit lower body weight and reduced hepatic lipid accumulation. Moreover, liver lipidomics analysis indicates the beneficial effect of PFAS on offspring hepatic lipid homeostasis. Offspring of PFAS exhibited altered gene expression patterns in the liver, with downregulation of several genes involved in lipid metabolism and inflammation signaling pathways. Mechanistically, whole genome bisulfite sequencing (WGBS) of paternal sperm revealed changes in gene expression of offspring liver depending on PFAS, including reproducibly increased methylation at the intron region of Acc1 and the promoter region of Scd1 , the key gene of lipid metabolism, in the liver of PFAS offspring. However, these epigenetic findings are exploratory and require confirmation with a larger sample size. Overall, this study provides the first evidence of beneficial effect of paternal folic acid administration on preventing NAFLD in the offspring.