Cadmium exposure is associated with impaired ovarian function: Potential role of cadmium-induced ferroptosis in granulosa cells

Cadmium (Cd) is a toxic environmental heavy metal with potential toxicity on the reproductive system. Cd-induced effects on ovarian function and the underlying mechanisms are unclear. This study integrated population-based and in vitro experiments to investigate the associations between environmental Cd exposure and ovarian dysfunction in reproductive-age women with infertility, and elucidated the potential molecular mechanisms involved. Elevated Cd exposure was significantly associated with lower serum estradiol levels and an inverted U-shaped relationship with anti-Müllerian hormone levels, suggesting diminished ovarian reserve. No significant associations were observed between Cd concentrations and in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) pregnancy outcomes. In vitro, Cd exposure dose-dependently impaired proliferation of KGN granulosa cells and induced cell death. Ferroptosis was characterized by GPX4 depletion, TFRC/ACSL4 upregulation, oxidative stress, lipid peroxidation, and Fe²⁺ accumulation, which were mitigated by the ferroptosis inhibitor ferrostatin-1. These findings suggest that environmental Cd exposure is associated with changes in levels of indicators of reduced ovarian reserve. Furthermore, Cd induces ferroptosis in granulosa cells in vitro, suggesting a plausible mechanistic link, highlighting a potential target for reducing environmental reproductive toxicity.