Chronic exposure to low-dose cadmium disrupts spermatogenesis in mice through ectoplasmic specialization damage

Cadmium (Cd) is a ubiquitous environmental pollutant threatening ecosystem stability and public health. Cd is also a known male reproductive toxicant that disrupts the blood-testis barrier, thereby inhibiting the spermatogenesis function. However, the mechanisms underlying Cd-inhibited spermatogenesis function remain largely unknown. Hereby, we established a mouse model exposed to environmentally relevant doses of Cd (1.45 and 7.25 mg Cd/(kg feed) through dietary supplementation for 24 weeks and conducted corresponding in vitro experiments to elucidate Cd-induced spermatogenesis dysfunction. Data first showed that chronic Cd exposure caused sperm quality decline and testicular damage. Ultrastructural observations further revealed the impairment of ectoplasmic specialization (ES) structure in Sertoli cells. Transcriptome analysis and subsequent verification experiments suggested that Cd-induced mixed lineage kinase domain-like protein (MLKL) activation and its resultant translocation to the endoplasmic reticulum (ER) triggered excessive ER stress. Finally, based on the correlation analysis, we identified that Cd-induced excessive ER stress resulted in ES disruption, leading to spermatogenesis dysfunction. In summary, this study reveals a new mechanism by which chronic environmental Cd exposure induces spermatogenesis dysfunction through MLKL-mediated ER stress, providing potential therapeutic targets for mitigating Cd-induced male reproductive toxicity.