Low folate status and related polymorphisms are associated with lower sperm quality in healthy men: The Led-Fertyl cross-sectional study

Background Folate-mediated one-carbon metabolism is essential for DNA synthesis, methylation and genomic integrity during spermatogenesis. Objective To study the associations between status in folate, cobalamin, homocysteine, single nucleotide polymorphisms affecting folate-mediated one-carbon metabolism and sperm quality. Methods In this cross-sectional study, 197 healthy men (18-40 years) were recruited between 2021-2023. Plasma folate, red blood cell folate, plasma cobalamin, total homocysteine, and single nucleotide polymorphisms affecting folate and cobalamin status were determined. Sperm quality parameters were assessed by WHO 2010 criteria. Associations between B-vitamin status, genetic polymorphisms, and sperm quality parameters were assessed using multivariable linear and logistic regression analysis. Results Median (P25, P75) plasma folate was 14.2 nmol/L (11.0, 17.8) and red blood cell folate was 678.2 nmol/L (582.3, 785.0). Deficiency, plasma folate <7 nmol/L and red blood cell folate (<340 nmol/L), occurred in 4.6% (95%CI: 2.4, 8.5) and 2.6% (95%CI: 1.1, 5.8) of participants, respectively. Lowest compared with highest tertile plasma folate (<11.9 vs ≥17.0 nmol/L) and RBCF (<625.0 vs ≥742.1 nmo/L) were associated with lower sperm count (B = -0.428, SE: 0.196 and B = -0.459, SE: 0.183, respectively) and higher odds of altered seminogram (OR = 3.367, 95% CI: 1.379, 8.220 and OR = 2.305, 95% CI: 1.002, 5.306, respectively). Median (P25, P75) plasma cobalamin was 239.1 (203.0, 282.3) pmol/L and plasma total homocysteine was 9.6 μmol/L (7.8, 11.5). Cobalamin deficiency (<148 pmol/L) and plasma total homocysteine >15 μmol/L were observed in 1.5% (95%CI: 0.5, 4.4) 5.6% (95%CI: 3.1, 9.7) of participants, respectively. Neither were associated with sperm quality parameters. The MTHFD1 1958AA compared with GG genotype was associated with reduced progressive motility (B = -7.732%, SE: 3.782), and higher odds of altered seminogram (OR = 4.388, 95%CI: 1.407, 13.687). Conclusion Low folate status is negatively associated with sperm quality. The MTHFD1 1958 AA genotype may be negatively associated with sperm quality.