Maternal exposure to polystyrene nanoplastics triggers ovarian injury in mice offspring: Ferroptosis mediated by the HIF-1α/HO-1 pathway.

The escalating environmental contamination by nanoplastics (NPs) poses potential risks to reproductive health, yet the intergenerational effects of maternal NPs exposure on offspring ovarian function remain poorly understood. In the current study, pregnant mice were orally administered polystyrene nanoplastics (PS-NPs) throughout gestation, resulting in impaired offspring growth and marked ovarian damage characterized by follicular structural disruption and steroidogenic dysfunction. Transcriptomic profiling of offspring ovaries revealed significant alterations in genes associated with follicle development, oxidative stress, lipid metabolism, and iron ion binding, with pathway analysis identifying ferroptosis and HIF-1 signaling as key affected pathways. Subsequent in vivo and in vitro validation demonstrated that PS-NPs triggered iron accumulation, lipid peroxidation (LPO), and dysregulation of ferroptosis-related proteins (ACSL4, FTH1, SLC7a11, and GPX4) in ovarian granulosa cells. Notably, PS-NPs activated the HIF-1α/HO-1 axis, and pharmacological inhibition of either ferroptosis by Ferrostatin-1 (Fer-1) or HIF-1α by LW6 effectively rescued cellular viability, restored hormone synthesis, and attenuated molecular markers of ferroptosis. Collectively, these findings demonstrate that maternal PS-NPs exposure induces ovarian dysfunction in offspring through HIF-1α/HO-1-mediated-ferroptosis, providing novel insight into the intergenerational toxicity of environmental NPs while identifying potential therapeutic targets for intervention.