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

Abstract

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-β-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-β1, TGF-βR1, 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-β, 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. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 414-422, 2019.