Paternal Cyanidin-3-O-Glucoside Diet Improved High-Fat, High-Fructose Diet-Induced Intergenerational Inheritance in Male Offspring's Susceptibility to High-Fat Diet-Induced Testicular and Sperm Damage.

High-fructose and high-fat diet (HFHFD) has been associated with impaired spermatogenesis, leading to decreased sperm quality and increased male infertility, with similar effects observed in offspring. Cyanidin-3-O-glucoside (C3G), a recognized food antioxidant, has shown promise in protecting in male reproduction and modulating epigenetic modifications. However, its potential role in ameliorating intergenerational inheritance induced by HFHFD remains underexplored. In this study, we investigated the effects of paternal HFHFD on reproductive injury of offspring and the protective effect of C3G. Paternal mice were subjected to 12 weeks of HFHFD induction and C3G treatment was conducted for 8 weeks. Offspring obtained via in vitro fertilization were fed either a normal diet (ND) or high-fat diet (HFD). Our findings indicate that while the paternal HFHFD did not result in observable reproductive impairments in paternal mice, it did affect offspring testicular function through intergenerational inheritance, rendering them more susceptible to testicular damage and reduced sperm counts when exposed to an HFD. Notably, C3G intervention significantly mitigated these effects, suggesting its potential as a therapeutic compound for alleviating the impact of paternal intergenerational inheritance on male fertility resulting from HFHFD. These results underscore the importance of further exploring the mechanisms underlying intergenerational inheritance and the potential of interventions such as C3G in mitigating its effects, with implications for both basic research and clinical practice.