Tributyltin affects the growth of ovarian granulosa cells in polycystic ovary syndrome by upregulating YY1-mediated CDKN1C via the PI3K/AKT pathway

Abstract

Polycystic ovary syndrome (PCOS) poses a significant threat to women's fertility and quality of life. Studies have found a close association between the environmental contaminant tributyltin (TBT) and the occurrence of PCOS. The main objective of this study was to investigate the specific mechanisms by which TBT adversely affects the growth of ovarian granulosa cells. Cell viability, cycle, proliferation, and apoptosis were measured by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2’-deoxyuridine (EdU), and flow cytometry. Simultaneously, lactate dehydrogenase (LDH) leakage and Caspase-3 activity were measured by the corresponding kits. Besides, western blot was used to analyze the protein levels of cyclin-dependent kinase inhibitor 1 C (CDKN1C) and the transcription factor Yin Yang 1 (YY1). TBT severely impaired the viability, cell cycle, and proliferation capacity of granulosa cells, and induced their apoptosis. Silencing CDKN1C and YY1 alleviated the damage caused by TBT to the cells, but these repair effects were weakened by CDKN1C overexpressed. By inhibiting the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, TBT upregulated the YY1-mediated CDNK1C, and further exacerbated the damage to granulosa cells. This study revealed the mechanism that TBT induced the loss of ovarian granulosa cells in PCOS patients by upregulating YY1-mediated CDKN1C expression, which provided new ideas and targets for the pathogenesis and treatment of PCOS.