The association of exposure to multiple metals with the risk of idiopathic oligoasthenoteratozoospermia: The mediating role of sperm chromatin.

BACKGROUND

The sperm DNA fragmentation index (DFI) is a crucial marker of single- or double-stranded DNA breaks, whereas the sperm high DNA stainability (HDS) indicates immature sperm nuclei accompanied with aberrant protein expression or altered protamine-to-histone ratios. Thus, sperm DFI and HDS constitute non-classical semen parameters that may serve as surrogate indicators of male fertility beyond what classical semen parameters (sperm motility, concentration and morphology) can offer. However, few epidemiological studies have investigated the impact of metal exposure on high sperm DFI and sperm HDS risk, especially their potential mediating roles in the association between metal exposure and risk of idiopathic oligo-asthenoteratozoospermia (iOAT). Against this background, this study was designed to explore the association of metal exposure in seminal plasma with the risk of high sperm DFI, high sperm HDS, and iOAT, as well as determine whether sperm DFI and sperm HDS mediate the relationship of metals with the risk of iOAT.

METHODS

A case-control study comprising 590 male participants (317 controls and 273 cases) was performed. Thirteen metals in seminal plasma (Fe, Ni, Cu, Co, Se, Sr, Cd, Cr, Pb, V, Mn, Tl, and Ba) were quantified using inductively coupled plasma mass spectrometer (ICP-MS). The individual effect of each metal on high sperm DFI, high sperm HDS, and iOAT risk was explored using multivariate logistic regression models. Quantile g-computation (Qgcomp) and Bayesian kernel machine regression (BKMR) were applied to dissect the combined effects of these metals on high sperm DFI, high sperm HDS, and iOAT risk. Moreover, we explored the potential mediating roles of sperm DFI and sperm HDS (both treated as continuous variables) in the association between metal exposure and iOAT risk using mediation analysis.

RESULTS

Using sperm DFI and sperm HDS as binary variables, multivariate logistic regression models showed that the second and third tertiles of Cr levels in seminal plasma were positively associated with high sperm DFI risk, with reference to the first tertile. Further analysis revealed that Sr and Tl levels in the third tertile were positively associated with high sperm DFI risk relative to the first tertile. Furthermore, Cr levels in the third tertile were positively associated with high sperm HDS risk, with the first tertile as the reference. Regarding the iOAT risk, elevated concentration of Ni, Cr, and Tl in the third tertile correlated with increased risk when compared to the first tertile. The Qgcomp and BKMR models consistently revealed that Sr and Tl levels in seminal plasma were positively associated with the high sperm DFI risk, V and Cr had a similar association with high sperm HDS risk, Tl, Ni and Cr exhibited a strong positive relationship with iOAT risk. Mediation analysis indicated that 63.29 % of the association between Tl exposure and the risk of iOAT was mediated by sperm DFI. In contrast, sperm HDS did not mediate the association between Cr and Ni exposure and the risk of iOAT.

CONCLUSIONS

This study demonstrates that exposure to metals may compromise sperm DNA integrity, increase the proportion of immature sperm nuclei, and the risk of iOAT. Specifically, elevated Cr levels in seminal plasma were consistently and positively associated with high sperm DFI, high sperm HDS, and iOAT risk. The results also indicated that sperm DFI mediated the association between Tl exposure and iOAT risk, but these mediating effects were not observed for sperm HDS on the relationship of Cr and Ni exposure with iOAT risk. This highlights the need for further investigations to clarify this complex relationship. Overall, our findings underscore the need to formulate environmental policies aimed at reducing exposure to harmful metals to promote male reproductive health.