Obesity modifies the association between serum homocysteine and sperm DNA fragmentation: a cross-sectional study of 5,032 men undergoing fertility evaluation

Sperm DNA fragmentation (SDF) provides information on sperm DNA integrity beyond conventional semen parameters. Homocysteine is a central intermediate in one-carbon metabolism and has been linked to metabolic and redox disturbances, but its association with SDF remains insufficiently defined. This study evaluated the association between serum homocysteine and SDF in men undergoing fertility evaluation. This cross-sectional study included 5,032 men undergoing their first fertility evaluation at a single reproductive center. Serum homocysteine was analyzed as a continuous variable, according to clinically defined hyperhomocysteinemia, and across tertiles. SDF was analyzed as a continuous outcome and as abnormal SDF, defined as 30% or higher. Body mass index was categorized as normal weight, overweight, or obesity. Conventional semen parameters were descriptively compared across homocysteine tertiles. Linear regression was used for continuous SDF, and logistic regression was used for abnormal SDF. Models were unadjusted and adjusted for age, sexual frequency, body mass index, and abstinence duration. Effect modification by body mass index category was evaluated using interaction analyses. Median SDF increased across homocysteine tertiles from 13.65% in the lowest tertile to 14.93% in the middle tertile and 17.10% in the highest tertile. The prevalence of abnormal SDF increased from 10.53% to 12.12% and 20.25%, respectively. Sperm concentration was comparable across tertiles, whereas total motility and normal morphology were lower in the highest tertile (both P < 0.001). After adjustment, each 1 µmol/L increase in homocysteine was associated with higher SDF (β = 0.132; 95% CI, 0.087–0.176) and greater odds of abnormal SDF (OR = 1.026; 95% CI, 1.017–1.034). Compared with the lowest tertile, the highest tertile was associated with higher SDF (β = 3.383; 95% CI, 2.621–4.145) and increased odds of abnormal SDF (OR = 2.184; 95% CI, 1.767–2.698). Body mass index category significantly modified the association, which was strongest among men with obesity (interaction P = 0.011). Higher serum homocysteine was associated with greater SDF and higher odds of abnormal SDF, with the strongest associations observed among men with obesity. These findings suggest serum homocysteine as a candidate metabolic correlate of sperm DNA integrity, particularly among men with obesity. Not applicable. This study was a cross‑sectional study and did not involve prospective assignment of participants to a medical or behavioral intervention.