Tributyltin-Induced Disruption of Acetylation-Related Proteins and Epigenetic Regulation in Sertoli Cells

Abstract

Objective: Acetylation-related proteins like CREB-binding protein (CBP), general control non-depressible 5 (GCN5), and P300/CBP-associated factor (PCAF) are critical for chromatin remodeling and transcriptional regulation, particularly affecting the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). This study examines how exposure to the environmental obesogen tributyltin (TBT) affects the expression of these key proteins in rat Sertoli cells (SCs), providing insight into potential epigenetic disruptions. TBT is a persistent organotin compound used in antifouling paints, plastics, wood preservatives, and agriculture. Human exposure occurs mainly through contaminated seafood, water, and dust. Methods: SCs were exposed for 24 hours to TBT at concentrations of 0.1 nM (sub-toxic), 10 nM, or vehicle control. We assessed protein levels of CBP, GCN5 and PCAF using Slot-Blot analysis. Results: Following exposure to 10 nM TBT, SCs exhibited an 8% increase in acetylated CBP (A-CBP) expression and a significant 50% reduction in total CBP levels, suggesting a disruption in the equilibrium of chromatin-modifying functions. In contrast, 0.1 nM TBT led to a modest 5% reduction in A-CBP and a 39% decrease in CBP expression, with both changes trending toward significance. GCN5 expression, a major histone acetyltransferase involved in gene activation, was markedly elevated (75%) at 10 nM TBT exposure, indicating a compensatory or stress-induced regulatory mechanism. Conversely, 0.1 nM TBT resulted in a slight, non-significant downregulation (10%) of GCN5. PCAF expression, another critical acetyltransferase and transcriptional coactivator, was reduced by 16% at 10 nM TBT and increased by 26% at 0.1 nM, with both changes showing near-significant trends. Conclusions: TBT alters the expression of acetylation-regulating proteins in a dose-dependent manner, potentially disturbing the epigenetic regulation of genes like PGC-1α. These findings suggest that environmental toxicants such as TBT may impair Sertoli cell function and male reproductive health by modulating the epigenetic landscape.