Bromodomain and extraterminal protein inhibitor JQ1 induces maturation arrest and disrupts the cytoplasmic organization in mouse oocytes under in vitro conditions

JQ1, a small cell-permeable molecule is known for its potent inhibitory action on bromodomain and extraterminal (BET) proteins. Although earlier studies have shown its inhibitory effect on male gametogenesis, limited information is available about its influence on oocyte development. Since BET genes are known to exhibit regulatory functions on oocyte development and maturation, the present study aimed to investigate the effect of JQ1 on oocyte developmental competence under in vitro conditions. Germinal vesicle (GV) stage oocytes were collected from adult Swiss albino mice and subjected to in vitro maturation (IVM) in the presence of various concentrations of JQ1 (25, 50, and 100 μM). The metaphase II (MII) stage oocytes were assessed for cytoplasmic organization and functional competence at 24 h after IVM. A significant decrease in nuclear maturation (at 50 and 100 μM), symmetric cytokinesis, altered distribution of mitochondria and cortical granules, poorly organized actin and meiotic spindle, misaligned chromosomes, and elevated endoplasmic reticulum (ER) stress and oxidative stress was observed in JQ1-exposed oocytes. Presence of N-acetyl cysteine (NAC), in IVM medium resulted in significant reduction in JQ1-induced oxidative stress and symmetric cytokinesis. Administration of JQ1 (50 mg/kg, intra peritoneal) to adult Swiss albino mice primed with pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (hCG) did not affect the ovulation. However, a high degree of oocyte degeneration, elevated intracellular reactive oxygen species (ROS), and GRP78 expression was observed in JQ1-administered mice. In conclusion, our study reveals that BET inhibitor JQ1 has detrimental effects on oocyte function and development.