Aluminum exposure induces ferroptosis in spermatogenic cells of mice through iron overload and lipid peroxidation.

Aluminum (Al) is a pervasive environmental contaminant with detrimental biological effects. Although Al exposure induces oxidative stress and toxicity in spermatogenic cells, leading to impaired male reproductive function, the underlying molecular mechanisms remain incompletely elucidated. In this study, we systematically evaluated the toxic effects of Al on spermatogenic cells using both in vivo and in vitro models. Transcriptomic profiling of GC-2spd cells revealed Al-induced differential gene expression related to oxidative stress response, iron homeostasis, and lipid metabolism regulation. These alterations were notably enriched in the ferroptosis and HIF-1 signaling pathways. Subsequent in vivo analyses demonstrated that Al exposure increased iron levels and oxidative stress while reducing ATP content in mouse testes, resulting in testicular damage, decreased sperm quality, and lowered serum sex hormone levels, all of which contribute to reproductive dysfunction. Further investigations confirmed that Al disrupts redox and iron homeostasis, promoting lipid peroxidation and ferroptosis in both mouse testes and GC-2spd cells. Importantly, administration of the ferroptosis inhibitor Ferrostatin-1 (Fer-1) effectively restored homeostasis, thereby alleviating Al-induced ferroptosis and spermatogenic cell toxicity. In conclusion, this study demonstrates that Al disrupts iron and redox balance, leading to iron accumulation and lipid peroxidation in spermatogenic cells, which triggers ferroptosis and ultimately causes male reproductive impairment. These findings identify ferroptosis as a novel therapeutic target for mitigating aluminum-related reproductive risks and provide a scientific basis for public health interventions in occupational and environmental settings grounded in this newly characterized cell death mechanism.