[Chronic iron overload induces diminished ovarian reserve in mice via iron metabolism dysregulation-mediated...

To investigate the mechanism by which chronic iron overload induces diminished ovarian reserve (DOR) in mice.

Forty female C57BL/6J mice with normal estrous cycles were randomly divided into 4 groups (n=10) for intraperitoneal injections of normal saline or iron dextran at 0.1, 0.5 or 1.0 g/kg once a week for 8 consecutive weeks. The changes in body weight and food intake of the mice were monitored weekly. Vaginal smears were used to assess estrous cycle changes of the mice, and wet weights of bilateral ovaries and uterus were recorded. Ovarian histopathology was evaluated by HE staining, iron deposition was detected by Prussian blue staining; serum levels of sex hormones (FSH, LH, E₂, and AMH) and the levels of MDA and SOD in the ovarian tissue were determined, and reactive oxygen species (ROS) production was assessed on frozen sections of the ovarian tissue. Mitochondrial ultrastructural changes in the ovaries of the mice were observed with transmission electron microscopy, and ovarian expression levels of Fth1, Ftl, Cat, Gpx1, Tf and Tfr1 mRNAs and Tf, Tfr1, Ft, Fth1, Ftl and Gpx4 protein were detected.

The mice receiving injections of 0.5 and 1.0 g/kg iron dextran exhibited disrupted estrous cycles, increased atretic follicles, decreased ovarian index, and increased uterine index with reduced AMH and E₂ levels and increased FSH and LH levels. The injections caused significant iron accumulation, oxidative stress, and obvious mitochondrial damage in the ovarian tissues, resulting also in downregulation of Tf, Tfr1, Gpx4, Gpx1 and Cat and upregulation of Ft, Ftl and Fth1 expressions.

Iron dextran at 0.5 and 1.0 g/kg can induce chronic, dose-dependent iron overload in mice, which causes systemic iron metabolism disorders and disrupted iron homeostasis to trigger oxidative stress damage and endocrine dysfunction and ultimately induce DOR.