Investigating the mechanism by which nonylphenol disrupts human sperm motility via network toxicology

The global incidence of male infertility is increasing annually, with environmental pollution identified as a significant contributing factor. Nonylphenol (NP), an emerging environmental pollutant characterized by high biological toxicity and limited biodegradability, has effects on male fertility and its underlying mechanisms that remain inadequately understood. This study conducted a systematic search of various databases, identifying 68 protein targets closely associated with NP and asthenozoospermia. GO and KEGG pathway enrichment analyses reveal that NP may impair human sperm function by disrupting endocrine resistance, prolactin signaling pathways, and hormone signaling pathways. Utilizing the STRING platform and Cytoscape software, the study further identified 10 core target proteins. The top three affinity scores for NP with protein targets, ranked from highest to lowest, were STAT3, ESR1, and ESR2. This study conducted a comprehensive investigation into the effects of varying concentrations of NP (1, 10, 100 nM) on human sperm motility and its underlying mechanisms through in vitro experiments. NP inhibits the motility of uncapacitated sperm and impairs the ability of capacitated sperm to penetrate viscous media, with the inhibitory effects being positively correlated with NP concentration. Further mechanistic analyses demonstrated that NP exposure leads to the downregulation of ESR1, Nrf2, SRC protein levels in sperm, and an increase in STAT3 phosphorylation, elevated intracellular ROS levels, and depolarization of the mitochondrial membrane potential. These results suggest that NP may exert its effects via the ESR1, STAT3, Nrf2 and SRC signaling pathways, inducing oxidative stress in sperm and ultimately impairing human sperm motility.