Generational insights into testicular toxicity: unravelling typical causes, diagnostics, and nutraceutical strategies

Transgenerational epigenetic inheritance has been increasingly linked with the onset of numerous metabolic and reproductive disorders. Testicular integrity, reflected in morphology, physiology, and biochemical functions, is essential to male fertility. However, environmental toxicants such as endocrine disruptors, heavy metals, and oxidative agents are increasingly linked to testicular toxicity, contributing to reduced sperm quality, hormonal dysregulation, infertility, testicular atrophy, and elevated cancer risk. Accordingly, evidence from mammalian, nematode, and insect models demonstrates that testicular toxicity often exerts its long-term effects through epigenetic mechanisms like DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. These heritable changes have been shown to disrupt testicular metabolism and reproductive outcomes across generations. Although emerging studies suggest the protective potential of nutraceuticals in ameliorating testicular damage, there is a lack of consensus on effective compounds, mechanisms of action, and long-term outcomes. In this narrative review, we explored insights from existing studies to highlight strengths, such as advances in understanding epigenetic pathways, and exposed gaps, including inadequate translational studies, dosage standardization, and a lack of multigenerational trials in humans. We provided an overview of current diagnostic challenges and proposed nutraceutical interventions with anti-inflammatory and antioxidant properties as viable preventive and therapeutic strategies. Importantly, we offered insights into the repurposing of bioactive compounds targeting key molecular pathways involved in testicular toxicity. Therefore, our review underscored the need for integrative studies focusing on the paternal origin of disease and lays the foundation for future research into nutraceutical-based epigenetic modulation to mitigate reproductive health risks across generations.