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.