Tolylfluanid induces oxidative stress-associated calcium dysregulation and mitochondrial dysfunction in porcine trophectoderm and uterine luminal epithelial cells

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Tolylfluanid is an aryl sulfamide fungicide widely used in agriculture and marine industries, but its effects on reproductive processes remain poorly understood. This study aimed to evaluate the cytotoxic effects of tolylfluanid and to investigate the mechanisms underlying its action via porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells. These cells are essential for early embryonic development and implantation. Tolylfluanid reduced cell viability in monolayer cultures and impaired spheroid formation in 3D cultures, accompanied by cell-cycle dysregulation and apoptosis. It disrupted intracellular calcium homeostasis, causing mitochondrial calcium overload and cytosolic depletion, along with mitochondrial depolarization and reduced oxygen consumption and ATP production. At the molecular level, tolylfluanid reduced Bcl-xL levels while increasing BAK, cytochrome c, and cleaved caspase-3 levels, supporting the involvement of mitochondria-mediated apoptosis. MAPK and PI3K signaling pathways were also activated. Tolylfluanid also increased intracellular ROS levels and lipid peroxidation, accompanied by mitochondrial dysfunction, impaired migration, and signaling alterations. Co-treatment with N-acetylcysteine (NAC) prevented tolylfluanid-induced oxidative stress, mitochondrial dysfunction, calcium imbalance, and loss of cell viability. Collectively, these findings indicate that oxidative stress is an important contributor to the interconnected cellular alterations induced by tolylfluanid, which may affect cellular functions associated with early pregnancy.

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