F-53B triggers ovarian granulosa cell senescence and ovarian dysfunction by triggering mitochondrial dysfunction

As a class of persistent organic pollutants, per-and polyfluoroalkyl substances (PFASs) are widely distributed in the global environment, posing potential threats to ecosystems and human health. 6:2 Chlorinated polyfluoroalkyl ether sulfonate (F-53B), a primary substitute for perfluorooctane sulfonic acid (PFOS), has been widely used and detected in human samples. However, current toxicological studies on F-53B mainly focus on organs such as the liver and intestines, while its effects on the female reproductive system-particularly ovarian function-remain incompletely understood. This work investigated the effects of F-53B on ovarian granulosa cells (COV434 and KGN cells) and ovarian function in mice, as well as its molecular mechanisms. In vitro results showed that F-53B exposure significantly promoted senescence of ovarian granulosa cells. Mechanistic studies revealed that F-53B induced senescence via the cGAS-STING-IRF3 signaling axis. Further analysis demonstrated that F-53B exacerbated senescence by inhibiting autophagy. In vivo studies showed that F-53B exposure caused ovarian dysfunction in mice, characterized by reduced follicular reserve, elevated serum follicle-stimulating hormone (FSH) levels, and decreased estradiol (E2) levels. Taken together, this work first reveals that F-53B induces senescence of ovarian granulosa cells through triggering innate immune signaling pathway, providing new experimental evidence for understanding the hazards of F-53B to female reproductive health. The findings not only provide critical data for the toxicity assessment of PFASs but also offer potential molecular targets for the prevention and intervention of premature ovarian failure.