Suppression of ovarian follicle development by nano TiO2 is associated with TGF-β-mediated signaling pathways

Nanoparticulate titanium dioxide (nano TiO2) is extensively applied in biological tissue engineering materials, food additives, cosmetics, and sunscreens. Numerous studies to date have demonstrated that nano TiO2 penetrates through the digestive system and possibly the blood circulation, leading to accumulation in the ovary and consequent reproductive toxicity. However, the mechanisms underlying the toxic effects of nano TiO2 on the female reproductive system remain to be established. In this study, female mice were exposed to different doses of nano TiO2 (1.25, 2.5, or 5 mg/kg body weight) via intragastric administration for 60 consecutive days, followed by investigation of follicular development, regulation of TGF-beta-mediated signaling pathways, and expression of the pathway components. Subchronic exposure to nano TiO2 induced a decrease in the number of primordial, secondary, and antral follicles and corpus luteum and concomitant increase in atretic follicles. Furthermore, follicular development disorder induced by nano TiO2 was associated with upregulation of TGF-beta 1, TGF-beta R1, PTEN, and Foxo3a involved in cell growth and apoptosis and downregulation of several growth factors (PI3K, AKT, p-mTOR, p70S6K, p-p70S6K1, rpS6, p-rpS6, TSC1, and TSC2) in mouse ovaries. Our data collectively implied that suppression of ovarian follicle development by nano TiO2 was triggered by dysfunction of the TGF-beta, PI3K/AKT/mTOR, and AKT/p70S6K-rpS6/TSC/mTOR pathways. The adverse effects of nano TiO2 on follicular development highlights the necessity for caution in the use of nanomaterials in the food industry. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 414-422, 2019.