Quercetin Protects Against T-2 Toxin-Induced Testicular Impairment by Mitigating NLRP3 Activation, Fibrosis, and Maintaining Testicular Homeostasis.
T-2 toxin is a prevalent mycotoxin that poses a substantial threat to male reproductive health, while effective protective strategies remain limited. This study evaluated the protective effects of quercetin (Qu), a natural flavonoid, against T-2 toxin-induced testicular injury and investigated the underlying mechanisms, focusing on NLRP3 inflammasome-associated inflammation and fibrotic remodeling. Male ICR mice were exposed to T-2 toxin (1 mg/kg) for 28 days, with or without Qu (50 mg/kg) or the NLRP3 inhibitor MCC950 (20 mg/kg). Testicular morphology, TLR4/MyD88/NLRP3 pathway activation, pyroptosis-associated molecular changes, fibrotic remodeling, and blood-testis barrier (BTB)-associated proteins were assessed using histological staining, immunofluorescence, immunohistochemistry, and Western blotting. T-2 toxin exposure caused marked testicular histopathological alterations and activated the TLR4/MyD88/NLRP3 pathway, accompanied by increased IL-1β and IL-18 levels and alterations in pyroptosis-associated molecular markers in Leydig and Sertoli cells (P < 0.05). These changes were associated with increased TGF-β1 expression and peritubular collagen deposition, suggesting early fibrotic remodeling (P < 0.05). T-2 toxin also reduced the expression of the BTB-associated proteins ZO-1, occludin, CX43, claudin-1, and β-catenin (P < 0.05). Qu treatment attenuated testicular pathological changes and inflammasome-associated inflammatory responses, reduced early fibrotic remodeling, and restored BTB-associated protein expression. MCC950 intervention further supported the involvement of NLRP3 inflammasome-associated signaling in T-2 toxin-induced testicular injury. Collectively, these findings suggest that Qu alleviates T-2 toxin-induced testicular injury, at least in part, by modulating NLRP3 inflammasome-associated inflammation and fibrotic remodeling, thereby maintaining testicular homeostasis. Qu may therefore have potential for mitigating mycotoxin-induced reproductive toxicity. Nevertheless, because the conclusions regarding pyroptosis are based primarily on pathway-associated molecular markers in a murine model, further studies incorporating direct assessments of pyroptotic cell death and validation in higher-order animal models and clinical settings are warranted.