Trophoblasts play a crucial role in embryo implantation and maintenance of normal pregnancy. Recently, oxidative stress has been considered as one important factor in the pathogenesis of spontaneous abortion and preeclampsia. Many studies have reported that the plasma levels of hydrogen peroxide (H2O2) are significantly increased in women with preeclampsia, but the mechanisms involved in H2O2-induced cell cytotoxicity in trophoblasts are still not completely explained. Our present study was undertaken to provide a united understanding of the role of oxidative stress generated by H2O2 on human trophoblasts and the underlying intracellular signaling pathways. Exposure to H2O2 resulted in a concentration-dependent growth decrease and apoptosis in human trophoblast-like JEG-3 cells. H2O2 treatment also caused intracellular reactive oxygen species (ROS) production and concomitant dissipation of the mitochondrial membrane potential. The three MAPK subfamilies, ERK1/2, JNK and p38 kinase, were all activated under H2O2-induced oxidative stress. Blocking the activation of JNK and p38 kinase increased cell viability and decreased apoptosis induced by H2O2 with their respective inhibitors, SP600125 and SB203580. However, preventing ERK1/2 activation further increased H2O2-induced cell death with U0126, an inhibitor of ERK upstream kinase MEK1/2. Taken together, these findings suggest that the mitochondria-dependent pathways and JNK-p38 kinase pathways are involved in H2O2-induced oxidative damage of human trophoblast-like JEG-3 cells, while ERK1/2 pathway may play an active role in cell survival following oxidant injury.
Keywords: H2O2; MAPKs; ROS; apoptosis; human trophoblasts; mitochondrial membrane potential.