Cadmium exposure induces Leydig cell injury via necroptosis caused by oxidative stress and TNF-α/TNFR1 signaling

Abstract

Cadmium, a ubiquitous environmental pollutant, has been linked to testicular damage, primarily through mechanisms such as oxidative stress and various forms of programmed cell death. Despite extensive studies on its toxic effects, the specific role of necroptosis in cadmium-induced reproductive toxicity remains unclear. In this study, we provide critical insights into how cadmium triggers necroptosis in Leydig cells, leading to testicular dysfunction. Using both in vitro and in vivo models, we demonstrated that cadmium exposure induces necroptotic cell death in Leydig cells, with significant involvement of the TNF-α/TNFR1 signaling pathway and reactive oxygen species (ROS) generation. Co-treatment with Nec-1, a specific necroptosis inhibitor, significantly reduced elevated ROS levels and suppressed TNF-α/TNFR1-induced necroptotic cell death, suggesting that ROS and the TNF-α/TNFR1 signaling pathway contribute to necroptosis activation in cadmium-induced Leydig cell injury. In conclusion, we demonstrate that necroptosis is a key driver of cadmium-induced testicular damage, suggesting that targeting necroptosis could offer novel therapeutic strategies for mitigating reproductive toxicity caused by heavy metals.