Adolescent exposure to Δ9-tetrahydrocannabinol (THC) impairs testicular function in young adult male mice

Cannabis use typically starts in early to mid-adolescence. Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, targets cannabinoid receptors (CBRs) to exert its pharmacological effects. Expression of CBRs has been observed in human and rodent testes, but their potential role in the control of reproductive function remains unclear. We aimed to elucidate how THC exposure during adolescence or young adulthood affects the reproductive health of males. C57BL/6N male mice were given THC (5 mg/kg) or vehicle, once daily by intraperitoneal (ip) injection from postnatal day (PND) 30 to PND 43 (adolescent exposure) or PND 70 to PND 83 (adult exposure), and testes were harvested at PND 70 and PND 110, respectively. Results showed that CBRs (CB1R and CB2R) and enzymes that biosynthesize or inactivate the endocannabinoid anandamide (AEA) -N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) or fatty acid amide hydrolase (FAAH), respectively-are expressed in the mouse testis. THC exposure in adolescence decreased sperm numbers and increased seminiferous tubule degeneration in young adult testes, while adult exposure did not affect spermatogenesis and seminiferous tubule morphology. Both adolescent and adult THC exposure resulted in decreased plasma testosterone levels; however, only mice with adolescent THC exposure showed impaired steroidogenesis with dysregulated expression of steroidogenic acute regulatory protein (StAR) and steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). Our results support that adolescent THC exposure may cause testicular toxicity through direct and aberrant activation of CBRs in the testis. These studies show that the adolescent testis is more sensitive than the adult testis to THC-induced disruption of spermatogenesis.