Epimedium promotes steroidogenesis by CREB activation-mediated mitochondrial fusion in endosulfan treated leydig cells

Epimedium, is used traditionally in Chinese medicine to treat infertility problems. In this study, we establish the cell model to elucidate the protective effect of epimedium against ES by analyzing the molecular relationship between mitochondrial dynamics and steroidogenesis and to explore the molecular mechanism focusing on mitochondria function relating to fertility. ES induced ROS accumulation in mitochondria and the epimedium treatment significantly reduced the ROS accumulation. Furthermore, mitochondria morphology was restored to elongated shape following epimedium treatment. Epimedium treatment promoted dynamin-associated protein 1 (Drp1)-mediated steroidogenesis pathway by upregulating PKA, CREB, Drp1, and StAR protein expression in response to ES exposure in Leydig cells. Moreover, it was also identified that, CREB plays an important role in epimedium activation in Drp1-mediated steroidogenesis signaling pathway by increasing, phospho-CREB expression in nucleus. Testosterone level is decreased in ES-exposed cells; however, the testosterone level was increased after epimedium treatment. In conclusion, epimedium treatment improved mitochondria function in ES-exposed Leydig cells and activated downstream Drp1-dependent steroidogenesis by CREB mediated signaling pathway.