In Vitro and In Vivo Pretreatment with Selenium Mitigates Tetrahydrocannabinol-Induced Testicular Cell Apoptosis: the Role of AKT and p53 Pathways.

Exocannabinoids such as tetrahydrocannabinol (THC) may alter the physiological function of endocannabinoids in male reproduction and thus affect male fertility. This study aimed to investigate the apoptotic effects of THC via mechanisms related to p53 and AKT signaling pathways on Sertoli cells and seminiferous germinal cells, as well as the possible protective role of selenium pretreatment in both in vitro and in vivo models. The Mus musculus Sertoli cell line, TM4, was used for in vitro experiments. The TM4 cells were cultured and exposed to selenium (2 μM, 48 h) and THC (470 μM, 24 h). The MTT test was performed to evaluate cell viability. Fifteen male Wistar rats (220 ± 20 g) were used for in vivo experiments and divided into three groups: (1) control, (2) tetrahydrocannabinol (THC, 5 mg/kg, dissolved in DMSO 5%, i.p., for 21 consecutive days), and (3) THC + selenium (selenium, 0.5 mg/kg per day, i.p.). At the end of the experiments, Sertoli cells and testis tissue samples were collected for biochemical (AKT, P53), cell apoptosis, and histological analyses. The results of the in vitro study revealed that THC significantly decreases the cell viability (p < 0.001) and expression of the p-AKt protein (p < 0.05) and increases Sertoli cells' apoptosis (p < 0.001) and p53 protein expression (p < 0.001). The in vivo effects of THC were in line with the in vitro results. Pretreatment with selenium (as sodium selenite) significantly decreased the THC-induced Sertoli cell and testicular tissue damages in the rats. Pathological changes were significantly alleviated in the selenium-pretreated rats. Collectively, these data suggest that pretreatment with selenium is able to protect against THC-induced testicular cell damage. The attenuating effect of selenium may be due to its anti-apoptotic activity through the p53 and AKT modulation.