Nicotinamide mononucleotide improves spermatogenesis in aluminium-exposed mice by inhibiting NLRP3-mediated pyroptosis

This study investigates the protective effects of nicotinamide mononucleotide (NMN) against aluminum-induced testicular dysfunction in mice. While previous research has demonstrated the general protective role of NMN in testicular function and highlighted the interaction between aluminum and the NLRP3 inflammasome, the precise mechanisms through which NMN mitigates aluminum-induced reproductive toxicity remain unclear. Our findings show that NMN protects Sertoli cells by inhibiting NLRP3-mediated pyroptosis, which subsequently improves spermatogenesis and testosterone synthesis. We also identify WT1 and GATA4 as key regulators involved in maintaining Sertoli cell integrity and function under aluminum-induced stress. This work provides new insights into the molecular mechanisms of aluminum-induced male infertility and underscores NMN's potential as a therapeutic strategy for preventing reproductive dysfunction caused by environmental toxicants, such as aluminum. Aluminum exposure disrupts spermatogenesis, yet no effective pharmacological interventions exist to treat aluminum-induced male infertility. In this study, we established an aluminum toxicity model in C57BL/6J mice through intragastric administration of AlCl3. We assessed the therapeutic effects of NMN by evaluating testicular histopathology, sperm quality, and serum reproductive hormone levels. Hematoxylin and eosin (H&E) staining revealed significant damage, including reduced seminiferous tubule diameter, disorganized germ cell layers, and a decreased number of germ cells and sperm. Sperm motility was significantly reduced, while the proportion of abnormal sperm increased. However, NMN treatment partially reversed these impairments. Transcriptomic analysis revealed significant upregulation of genes involved in the NLRP3 inflammasome and apoptosis pathways (e.g., NLRP3, GSDMD, caspase-1, and IL-1β) in the AlCl3-exposed group. NMN treatment mitigated testicular damage, suppressed NLRP3-mediated pyroptosis in Sertoli cells, and restored serum testosterone levels. Additionally, NMN treatment preserved the expression of key testicular proteins, including WT-1 GATA4, and vimentin. In summary, our study uncovers a novel mechanism by which aluminum exposure impairs spermatogenesis via NLRP3-mediated pyroptosis in testicular cells. We also demonstrate for the first time that NMN can ameliorate aluminum-induced reproductive dysfunction by inhibiting this pathway, offering a potential therapeutic strategy for aluminum-associated male infertility.