Cadmium exposure during puberty damages testicular development and spermatogenesis via ferroptosis caused by intracellular iron overload and oxidative stress in mice

Cadmium (Cd) is a widespread environmental pollutant and a reproductive toxicant. It has been proved that Cd can reduce male fertility, however, the molecular mechanisms remain unveiled. This study aims to explore the effects and mechanisms of pubertal Cd exposure on testicular development and spermatogenesis. The results showed that Cd exposure during puberty could cause pathological damage to testes and reduce sperm counts in mice in adulthood. Moreover, Cd exposure during puberty reduced GSH content, induced iron overload and ROS production in testes, suggesting that Cd exposure during puberty may induce testicular ferroptosis. The results in vitro experiments further strengthened that Cd caused iron overload and oxidative stress, and decreased MMP in GC-1 spg cells. In addition, Cd disturbed intracellular iron homeostasis and peroxidation signal pathway based on transcriptomics analysis. Interestingly, these changes induced by Cd could be partially suppressed by pretreated with ferroptotic inhibitors, Ferrostatin-1 and Deferoxamine mesylate. In conclusion, the study demonstrated that Cd exposure during puberty maybe disrupted intracellular iron metabolism and peroxidation signal pathway, triggered ferroptosis in spermatogonia, and ultimately damaged testicular development and spermatogenesis in mice in adulthood.