Downregulation of vdac2 inhibits spermatogenesis via JNK and P53 signalling in mice exposed to cadmium

Previous studies have reported the reproductive toxicity of cadmium (Cd); however, the effect of Cd on spermatogenesis and the underlying mechanism remain to be elucidated. In this study, mouse Leydig TM3 cells were treated with CdCl₂ (0, 5, 10 and 50 μM) for 24 h to evaluate cytotoxicity, and C57BL/6 mice were treated intragastrically with 0.4 mL CdCl₂ (0, 0.01, 0.05 and 0.1 g/L) for 2 months to investigate changes in spermatogenesis. The results showed that Cd aggravated apoptosis and proliferation in a dose-dependent manner, concomitant with deteriorated spermatogenesis and testosterone synthesis. For mechanism exploration, RNA-seq was used to profile alterations in gene expression in response to Cd, and the results indicated focus on P53/JNK signalling pathways and membrane proteins. We found that P53/JNK signalling pathways were activated upon Cd treatment, with the Cd-triggered downregulation of the vdac2 gene. P53/JNK pathway blockade ameliorated the Cd-induced inhibition of steroidogenic acute regulatory protein (STAR) expression and testosterone synthesis. Additionally, vdac2 knockdown in TM3 cells contributed to the phosphorylation of JNK/P53 and reduced the testosterone content. Vdac2 overexpression rescued the aforementioned Cd-induced events. Collectively, our study identified an innovative biomarker of Cd exposure in mice. The results demonstrated that vdac2 downregulation inhibits spermatogenesis via the JNK/P53 cascade. This finding may contribute to our understanding of the regulatory mechanism of Cd reproductive toxicity and provide a candidate list for sperm abnormality factors and pathways.