Leydig cells pyroptosis in testis mediates deoxynivalenol-induced male reproductive toxicity in mice

Deoxynivalenol (DON) is a toxic secondary metabolite produced by Fusarium spp. It is widely distributed among various cereals and has attracted much attention as a potential health threat to humans and domestic animals. However, the effects of DON on the reproductive systems of mammals are still ambiguous. In this study, the toxic effects of DON in the male reproduction of mice were investigated. The results showed that DON caused the shedding of sperm cells at all testis levels and the presence of inflammatory cells in the testicular interstitium. The rate of living sperm was significantly reduced, and the rate of sperm deformity was increased after DON exposure. The DON exposure resulted in decreased levels of testosterone (T) and increased levels of folliclestimulating hormone (FSH) and luteinizing hormone (LH) in the serum. Measurements of oxidative stress markers showed that DON induced oxidative stress in mice testis. Meanwhile, DON triggered the assembly of NLRP3-ASC-Caspase-1 inflammatory complex and pyroptosis in both mice testis and TM3 cells, further causing the activation of GSDMD, promoting the leakage of inflammatory cytokines, including IL-1 beta and IL-18. Notably, the inhibition of oxidative stress was found to protect pyroptosis in TM3 cells exposed to DON. We identified a novel mechanism of reproductive damage induced by DON, demonstrating the activation of the canonical Caspase-1-dependent pyroptosis pathway and clarifying the protection of antioxidation against pyroptosis damage. Our discovery provided support for the risk assessment of DON and target exploration for clinical treatment related to pyroptosis.