Low folate status and related polymorphisms are associated with lower sperm quality in healthy males: The Lifestyle and Environmental Determinants of Seminogram and Other Male Fertility-Related Parameters (Led-Fertyl) cross-sectional study.

BACKGROUND

Folate-mediated one-carbon metabolism is essential for deoxyribonucleic acid synthesis, methylation, and genomic integrity during spermatogenesis.

OBJECTIVES

To study the associations between the status of folate, cobalamin, homocysteine, single nucleotide polymorphisms (SNPs) affecting folate-mediated one-carbon metabolism, and sperm quality.

METHODS

In this cross-sectional study, 197 healthy males (18‒40 y) were recruited between 2021 and 2023. Plasma folate, red blood cell folate (RBCF), plasma cobalamin, total homocysteine, and SNPs affecting folate and cobalamin status were determined. Sperm quality parameters were assessed by World Health Organization 2010 criteria. Associations between B-vitamin status, genetic polymorphisms, and sperm quality parameters were assessed using multivariable linear and logistic regression analysis.

RESULTS

Median (25th and 75th percentiles) plasma folate was 14.2 (11.0, 17.8) nmol/L, and RBCF was 678.2 (582.3, 785.0) nmol/L. Deficiency, plasma folate <7 nmol/L and RBCF (<340 nmol/L), occurred in 4.6% [95% confidence interval (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 nmol/L compared with ≥17.0 nmol/L) and RBCF (<625.0 nmol/L compared with ≥742.1 nmo/L) were associated with lower sperm count [B = ‒0.428, standard error (SE): 0.196 and B = ‒0.459, SE: 0.183, respectively] and higher odds of altered seminogram [odds ratio: (OR): 3.4; 95% CI: 1.4, 8.2 and OR: 2.3; 95% CI: 1.0, 5.3, respectively]. Median (25th and 75th percentiles) plasma cobalamin was 239.1 (203.0, 282.3) pmol/L and plasma total homocysteine was 9.6 (7.8, 11.5) μmol/L. Cobalamin deficiency (<148 pmol/L) and plasma total homocysteine >15 μmol/L were observed in 1.5% (95% CI: 0.5%, 4.4%) and 5.6% (95% CI: 3.1%, 9.7%) of participants, respectively. Neither was associated with sperm quality parameters. The MTHFD1 1958AA compared with GG genotype was associated with reduced progressive motility (B = ‒7.7%, SE: 3.8), and higher odds of altered seminogram (OR: 4.4; 95% CI: 1.4, 13.7).

CONCLUSIONS

Low folate status is negatively associated with sperm quality. The MTHFD1 1958AA genotype may be negatively associated with sperm quality.