Endocrine-disrupting effects of titanium dioxide nanoparticles on the female reproductive system: Evidence from an ovariectomized rat model

Background: Titanium dioxide nanoparticles (TiO2NPs) are widely used metal nanoparticles capable of accumulating in tissues and exerting endocrine-disrupting effects. Their impact on female reproductive physiology remains largely unclear. This study aimed to elucidate the endocrine-disrupting properties of TiO2NPs by assessing ovarian and uterine histology, serum hormone levels, estrous cycle changes, and receptor expression patterns in both intact and ovariectomized female rats. Methods: Thirty-two Sprague Dawley rats were randomly divided into four groups (n = 8/group): intact control, intact TiO2NP (10 mg/kg/day, oral, 30 days), ovariectomized control (OvX), and OvX + TiO2NP (10 mg/kg/day, oral). Vaginal cytology was monitored for 10 days. ELISA measured serum estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels. Ovarian and uterine tissues were examined histologically and immunohistochemically for estrogen-receptor alpha (ER alpha), estrogen-receptor beta (ER beta), luteinizing hormone receptor (LHR), and follicle-stimulating hormone receptor (FSHR) expression. Results: TiO2NP exposure elevated estradiol levels in both intact and ovariectomized rats. While ovariectomy significantly increased LH and FSH, TiO2NP treatment normalized these levels in OvX rats. Ovarian changes included an increase in atretic follicles and a reduction in hormone receptor expression, whereas uterine tissues showed greater gland number, endometrial thickness, and receptor positivity. Estrous cycles were absent in OvX rats but reappeared with prolonged length and estrus frequency in the OvX + TiO2NP group. Conclusion: TiO2NPs exert estrogen-like effects and modulate gonadotropin release through the hypothalamic-pituitary axis, even without ovarian estrogen, indicating pronounced endocrine-disrupting effects on the female reproductive system.