Sulfur dioxide increases testosterone biosynthesis by activating ERK1/2 pathway and disrupting autophagy in Leydig cells

Sulfur dioxide (SO2) is a ubiquitous environmental pollutant that has been shown to be toxic to the male reproductive system, but the underlying mechanism remains unclear. Therefore, the SO2-treated mice and primary Leydig cell models were established to investigate the effects of SO2 on the production of testosterone and its specific mechanism. The results demonstrated that SO2 activated the ERK1/2 signaling pathway, leading to increased key proteins expression of testosterone biosynthesis and elevated testosterone levels. The addition of ERK1/2 inhibitor U0126 attenuated SO2-induced increases in key testosterone biosynthetic gene mRNA levels of Star, Cyp17a1, Hsd3b1, and testosterone. Low doses of SO2 reduced the expression of BECLIN1 and LC3 proteins, increased P-4E-BP1 protein expression, and decreased autophagy in Leydig cells. Moreover, increasing doses of SO2 correlate with enhanced Leydig cell autophagy and testosterone levels initially. However, increasing the dose of SO2 resulted in a significant decrease in cell viability and ultimately decreased testosterone levels. These findings suggest that SO2 promotes testosterone production by activating ERK1/2 and disrupting autophagy. This study enriched the dose-effect relationship of SO2 on the male reproductive system and provided a theoretical reference for us to have a comprehensive and dynamic understanding of the SO2 toxic mechanism.