The dual role of inflammatory microenvironment in modulating the effect of red blood cell folic acid on sperm DNA integrity: A retrospective study

The role of folic acid in male reproductive health remains incompletely understood, with existing findings presenting conflicting results. Reproductive tract inflammation, a key factor influencing semen quality, may modulate the effects of folic acid on semen parameters. However, this hypothesis remains unverified in a systematic manner. This retrospective study enrolled 98 men. Red blood cell folic acid levels, seminal plasma elastase, and semen parameters were measured. Polynomial regression models were employed to analyze nonlinear relationships and interaction effects, while machine learning methods were applied for model validation. The research found that the impact of red blood cell folate on semen quality is parameter-specific: it shows a significant U-shaped relationship with the sperm DNA fragmentation index (quadratic term β = 2.560 × 10⁻⁴, p = 0.015), and this relationship is significantly modulated by the inflammatory state (interaction term β = 2.825 × 10⁻⁷, p = 0.035), while it shows a stable linear positive correlation with the sperm forward motility rate (β = 0.024, p = 0.015), and is affected by age. Machine learning analysis further verified the core position of folate and inflammatory indicators in predicting semen quality. The effects of folic acid on semen quality are multifaceted. Its U-shaped influence on sperm DNA integrity is finely modulated by the inflammatory microenvironment, while simultaneously enhancing sperm motility. These findings suggest that clinical folic acid intervention strategies should consider the distinct responses of specific semen parameters and individual inflammatory states, offering novel insights into the precise prevention and treatment of male infertility.