Acute cadmium exposure damaged granulosa cell structure and blocked oocyte maturation via ferroptosis caused by intracellular iron overload and oxidative stress in mice

Cadmium (Cd) is a toxic heavy metal that can cause ovarian damage, but the mechanism is unknown. Ferroptosis is a newly identified type of programmed cell death. In our study, we explored whether ferroptosis is involved in Cd-induced ovarian damage and the underlying mechanism. Our histopathological results after acute Cd exposure showed significant damage to granulosa cells, and superovulation results showed that the first polar body extrusion (PBE) rate and the number of MII oocytes were significantly reduced. Transcriptomics analysis showed differences in lipid metabolism and amino acid pathways in the ovaries of Cd-exposed mice. Targeted metabolomics showed that oxidized ARA metabolites were increased in the ovaries of Cd-exposed mice. Further examination of oxidative markers revealed oxidative stress and abnormal iron metabolism in Cd-exposed mouse ovaries. Ultrastructure results showed that mitochondria of oocytes from Cd-exposed mice were significantly crumpled, cristae disappeared and showed an ferroptosis morphology. Further findings showed that acute Cd exposure up-regulated the mRNA and protein levels of the Acsl4 gene and down-regulated the mRNA and protein levels of the Gpx4 and Fsp1 genes, suggesting that Cd exposure induces ovarian ferroptosis. Ferritin-1 (Fer- 1), a specific inhibitor of ferroptosis, significantly alleviated ovarian oxidative stress and ferroptosis in mice and partially attenuated Cd-induced ovarian damage. In summary, Cd exposure leads to ovarian injury by inducing ovarian ferroptosis in mice. Our study provides a theoretical basis for finding potential strategies for Cd-related ovarian diseases based on ferroptosis process intervention.