Metabolic and antioxidant imbalance in Sertoli cells induced by tributyltin exposure is accompanied by Sirt3 downregulation.

Tributyltin (TBT), an environmental obesogen and endocrine disruptor that can accumulate in the food chain, impairs Sertoli cell (SC) function, yet its impact on the redox-regulating SIRT1/PGC-1α/SIRT3 axis remains uncharacterized. This study elucidates TBT-induced disruptions in SC redox homeostasis via this molecular axis. Primary cultures of juvenile rat SCs were exposed to environmentally relevant TBT concentrations (0.1 nM, 10 nM) for 24 h. Metabolic fluxes were quantified via 1H-NMR. Antioxidant capacity, glutathione peroxidase/reductase activities (GPx/GR), and oxidative damage markers (4-HNE, protein carbonylation) were assessed. Protein levels of SIRT1, PGC-1α, and SIRT3 were evaluated by slot blot. TBT at 0.1 nM reduced glucose consumption by 59% (p = 0.03), while 10 nM TBT elevated alanine production by 94% (p = 0.04), lowering the lactate/alanine ratio. Total antioxidant capacity declined by 45-55% (p < 0.05). SIRT3 levels decreased by 19% and 24% (p < 0.05) in SCs exposed to TBT 10 and 0.1 nM, respectively, whereas SIRT1/PGC-1α remained unchanged. GR activity increased in both groups of SC exposed to TBT (p < 0.05), with no alterations in GPx, lipid peroxidation, or protein carbonylation. TBT disrupts SC redox equilibrium via SIRT3 downregulation and impaired antioxidant capacity, which is partially mitigated by GR upregulation, highlighting the SIRT1/PGC-1α/SIRT3 axis as a target in TBT-induced reproductive toxicity.