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

Abstract

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.