Exploring the mechanism of carbamazepine decreasing testosterone levels based on cAMP/PKA/CREB pathway

The aim of this study was to explore the molecular mechanisms underlying carbamazepine (CBZ)—induced testicular toxicity and testosterone reduction in rats. For this purpose, Sprague–Dawley (SD) rats were intervened with 200 mg/kg CBZ for 12 weeks, and R2C cells were exposed to CBZ at concentrations of 0.5, 1 and 1.5 mM for 24 h. HE, Tunel, ELISA, immunofluorescence staining, RT-qPCR, and western blot were used to reveal the effects of CBZ on spermatozoa quality, testicular tissue structure, testosterone level and testosterone synthesis-related enzymes in rats. The results showed that CBZ significantly damaged the testicular tissue structure of rats, induced cell apoptosis, down-regulated the gene and protein expression levels of testosterone synthesis-related enzymes (STAR, TSPO, 17β-HSD and 3β-HSD), inhibited the expression of related proteins in the cAMP/PKA/CREB signalling pathway, and suppressed testosterone levels. In addition, the use of Db-cAMP (a PKA activator) significantly upregulated the protein expressions of PKA and p-CREB, evidently alleviated the CBZ-induced decrease in testosterone levels. In conclusion, CBZ induced testosterone resynthesis by inhibiting the cAMP/PKA/CREB pathway, affecting the expression of steroid synthesis-related enzymes and reducing testosterone levels.