Effect of paternal resveratrol intake on mitochondria and telomere length in mouse embryos and offspring

Advanced paternal age affects embryonic development and offspring phenotypes. We previously demonstrated that resveratrol prevents age-associated declines in the mitochondrial DNA copy number (mt-cn) and telomere length (TL) in embryos. The present study was performed to investigate the effects of paternal resveratrol intake on the mt-cn and TL in pups and embryos produced either via in vitro fertilization (IVF) or IVF using sperm preincubated in epididymal fluid (EF). C57BL/6N male mice were administered drinking water containing either the vehicle (ethanol, 1/2500) or 0.1 mM resveratrol. When these males were mated with young ICR females, paternal resveratrol treatment did not affect the mt-cn or TL in offspring derived from young fathers (16-25 weeks of age). In contrast, in offspring of aged fathers (41-51 weeks of age), the mt-cn and TL in heart tissue were altered in a sex-dependent manner. Moreover, continuous resveratrol administration to males until an advanced paternal age resulted in sperm TL elongation. However, resveratrol treatment did not affect the TL in embryos but significantly increased the mt-cn and reduced the lipid content in blastocysts produced via IVF using oocytes from young females (4 weeks of age). RNA- sequencing revealed that resveratrol treatment affected metabolic pathways, including lipid metabolism. The preincubation of sperm from young untreated males (11 weeks of age) in EF derived from resveratrol-treated males did not affect the mt-cn or TL in blastocysts but reduced the lipid content. In conclusion, paternal resveratrol intake modulates embryonic and offspring phenotypes, potentially through alterations in sperm TL, sperm epigenetic modifications, and bioactive components in EF. Resveratrol intake may exert long-term effects on offspring.