Aberrant DNMTs Promote TXNIP Upregulation and Ovarian Fibrosis in PCOS

Hyperandrogenism and elevated thioredoxin-interacting protein (TXNIP) are potential causes of infertility in women with polycystic ovary syndrome (PCOS). Epigenetic regulation of TXNIP mediates oxidative stress and inflammatory activation. However, the precise mechanisms including epigenetic regulation in PCOS are poorly understood. In this study, aberrant TXNIP in dehydroepiandrosterone (DHEA)-induced rat PCOS ovaries and dihydrotestosterone (DHT)-induced PCOS primary granulosa cells (GCs) coincided with a marked increase of DNA methyltransferases (DNMTs); this aberrant TXNIP triggers the release of pro-fibrotic factors, such as collagen I, α-SMA, and TGF-β, from GCs. Administration of the DNMT inhibitor 5-Aza downregulated TXNIP expression and improved the aberrant expression of the pro-fibrotic factors in PCOS-like ovaries and DHT-treated GCs. Furthermore, MG132, a proteasome inhibitor, attenuated the inhibitory effect of 5-Aza on DHT-induced TXNIP upregulation. Our data suggest that DNMT activation, by suppressing proteasome activity, contributes to increases in TXNIP expression, resulting in ovarian fibrosis and GC dysfunction in PCOS-like ovaries after exposure to hyperandrogenism.