Flutriafol disrupts trophoblast function: mitochondrial dysfunction mediated cell cycle arrest and apoptosis

Abstract

BackgroundFlutriafol, a triazole fungicide, is highly stable in the environment but can be harmful due to exposure to non-target species through different pathways.ObjectivesThis study aims to investigate the effect of flutriafol on human trophoblast cells (HTR-8/SVneo) and human choriocarcinoma cells (JEG-3).ResultsFlutriafol reduced the survival rate of both cells in a concentration-dependent manner (0-100 mu g/mL) and significantly inhibited their migration ability at 30 mu g/mL. Flutriafol treatment caused G0/G1 cell cycle arrest in HTR-8/SVneo cells, sub-G0 increase in JEG-3 cells and apoptotic cell death in both cells. Further, flutriafol inhibited mitochondrial electron transport chain complex expression, impaired mitochondrial membrane potential and induced mitochondrial Ca2+ overload to activate mitochondrial-dependent apoptosis pathways. The increased BAX and BAK expression accompanied these mechanisms, thereby improving apoptosis signals. Consequently, flutriafol multifacetedly impairs mitochondrial function in trophoblast cells, indicating that it may negatively affect implantation and placental development by inhibiting cell cycle progression and inducing apoptotic cell death.ConclusionThis study is the first to indicate that flutriafol may be harmful to human female reproductive health, emphasizing the need for further in vivo studies to comprehensively evaluate its toxic and environmental impact.