Nano-sized titanium dioxide exposure induces non-hyperandrogenic polycystic ovarian syndrome in rats by increasing aromatase and apoptosis in granulosa cells

Polycystic ovarian syndrome (PCOS) is a frequently encountered disease with hormonal and metabolic dysfunction in women of reproductive age. Nano-sized titanium dioxide (nTiO₂) has been widely used in skin care products, paints, food, and cosmetics. In this study, we found a substantial elevation of Ti in the follicular fluid of females diagnosed with non-hyperandrogenic PCOS (non-HA PCOS). Therefore, we orally subjected female rats to nTiO₂ at 10 and 100 mg/kg body weight for 10 weeks. We found that nTiO₂ triggered non-HA PCOS-like symptoms, including the increase of cystic follicles, estrous cycle disorder, and abnormal ovulation, but without high testosterone. By transcriptome sequencing, we identified that nTiO₂ exposure inhibited the steroid hormone synthesis and activated the pro-apoptotic pathways. Upon validating these altered pathways, we discovered that aromatase (Cyp19a1) overexpression contributed to the decline in testosterone/estradiol ratio. Meanwhile, the apoptosis of granulosa cells was increased by nTiO₂ exposure, which might result in the disorder of follicular development. This study presents the evidences revealing a pronounced correlation between nTiO₂ exposure and the emergence of non-HA PCOS, urging people to promote the safe utilization of nTiO₂.