Exposure of adult mice to perfluorobutanesulfonate impacts ovarian functions through hypothyroxinemia leading to down-regulation of Akt-mTOR signaling

Perfluorobutanesulfonate (PFBS), a short-chain perfluoroalkyl substance, is used in many industrial products. Preliminary evidence suggests that exposure to PFBS may increase the risk of infertility. The aim of this study was to investigate the influence of PFBS on ovarian function. Herein, we show that exposure of adult female mice to PFBS (200 mg/kg/day) (PFBS-mice) caused a decrease in the levels of serum total triiodothyronine and thyroxine, which depended on the activation of peroxisome proliferator-activated receptor alpha (PPAR alpha). The numbers of secondary, early antral and antral follicles were reduced in PFBS-mice with an increase in the atretic follicles, and these changes were recovered by the replacement of L-thyroxinein or the treatment with PPAR alpha antagonist GW6471. PFBS-induced hypothyroxinemia led to a decrease in the levels of Akt, mTOR and p70S6K phosphorylation in ovarian granular cells and cumulus cells, which suppressed the proliferation of these cells and enhanced autophagic death of granular cells and cumulus cells. The levels of serum estradiol and progesterone were reduced in PFBS-mice with a low expression of the steroidogenic genes Star and P450scc in ovarian tissues, which were sensitive to the replacement of L-thyroxinein or the blockade of PPAR alpha. The results indicate that exposure to PFBS (>= 200 mg/kg/day) through reducing thyroid hormones causes down regulation of Akt-mTOR signaling in granular cells and cumulus cells, leading to the deficits in the development of follicles and the biosynthesis of ovarian hormones. (C) 2019 Elsevier Ltd. All rights reserved.