Selenium protects granulosa cells from 3-nitropropionic acid-induced oxidative toxicity by regulating TRPM2-induced cell death.

TRPM2 channel stimulation-mediated excessive Ca2+ influx causes granulosa cell death and oxidative stress, which is a key factor in the onset of 3-nitropropionic acid (3NPA)-induced follicular atresia. Selenium (Se) could protect granulosa cells against reactive free oxygen species (ROS)-induced injury. This study investigated the effect of Se on 3NPA-induced oxidative stress and apoptosis in granulosa cells, with a specific focus on the inhibition of the TRPM2 channel. Four groups, control, Se (sodium selenite), 3NPA, and 3NPA + Se, were established in a mouse model. The same experimental groups were reproduced in vitro using human KGN granulosa cells. In KGN cells, the 3NPA group exhibited an increase in ADP-ribose-induced TRPM2 current density and H2O2-induced Ca2+ levels. These increases were not observed in the Se, 3NPA + Se, TRPM2 antagonist, and PARP-1 inhibitor groups. Treatment with Se and a TRPM2 antagonist enhanced the viability of mouse granulosa cells and elevated antioxidant levels (glutathione, glutathione peroxidase, and vitamin E) in the liver, plasma, red blood cells, and uterus. These effects were associated with reductions in 3NPA-induced apoptosis, caspase activities (-3, -8, and -9), mitochondrial membrane dysfunction, lipid peroxidation, and ROS. In conclusion, Se treatment decreased 3NPA-induced oxidative stress, apoptosis, and Ca2+ influx in granulosa cells by blocking TRPM2 channel activation and supporting the antioxidant redox system. These findings suggest that Se may serve as a potential therapeutic agent for modulating TRPM2 activity to reduce oxidative damage and prevent granulosa cell death.