Exogenous Metals Indirectly Affect Human Semen Quality via Immune Cells at Single-Cell Resolution

Immune modulation is crucial for male reproduction and fertility. Metals and metalloids (metals) have been extensively studied for their immunomodulatory effects. Whether metal exposure affects semen quality through immune modulation is unclear. In the present study, we explored the associations between exogenous metals within immune cells, immune cell proportions, and semen quality among 84 healthy men who repeatedly provided 266 semen samples over 90 days. We employed mass cytometry (CyTOF) technology to identify immune cells in semen and measured exogenous metals in these cells at the single-cell resolution. After adjusting for potential confounders, most detected metals in immune cells were inversely associated with the proportion of immune cells in semen samples (all <i>p</i> < 0.05), indicating the adverse effects of exogenous metals on immune cells. The proportion of immune cells showed N-shaped, nonlinear associations with sperm concentration, total count, progressive motility, and total motility. Mediation analyses showed that the percentage of indirect effects of exogenous metals on sperm quality parameters via immune cells ranged from 15.11% to 54.29%. Overall, our findings unravel the indirect effects of exogenous metal exposure on male reproductive health via immune cells, contributing valuable insights into the complex interplay between environmental factors, immune cells, and human semen quality.