Lim Jinhwan, Quach Caitlin, Nguyen Julie, Rizk Andrew, Getze Samantha, Jung Kwang-Mook, Mahler Stephen V, Piomelli Daniele, Luderer Ulrike
Departments of Environmental and Occupational Health, University of California Irvine, Irvine, CA, 92697.
Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA, 92697.
Toxicol Sci. 2025 Mar 24. doi: 10.1093/toxsci/kfaf035.
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.
大麻的使用通常始于青少年早期至中期。Δ9-四氢大麻酚（THC）是大麻的主要精神活性成分，作用于大麻素受体（CBRs）以发挥其药理作用。在人类和啮齿动物的睾丸中已观察到CBRs的表达，但其在生殖功能控制中的潜在作用仍不清楚。我们旨在阐明青春期或成年早期接触THC如何影响雄性的生殖健康。从出生后第30天（PND）至第43天（青春期接触）或第70天至第83天（成年接触），每天通过腹腔内（ip）注射给予C57BL/6N雄性小鼠THC（5mg/kg）或赋形剂，并分别在PND 70和PND 110采集睾丸。结果表明，CBRs（CB1R和CB2R）以及分别生物合成或使内源性大麻素花生四烯酸乙醇胺（AEA）失活的酶——N-酰基磷脂酰乙醇胺磷脂酶D（NAPE-PLD）或脂肪酸酰胺水解酶（FAAH）——在小鼠睾丸中表达。青春期接触THC会减少成年早期睾丸中的精子数量并增加生精小管退化，而成年期接触则不影响精子发生和生精小管形态。青春期和成年期接触THC均导致血浆睾酮水平降低；然而，只有青春期接触THC的小鼠表现出类固醇生成受损，类固醇生成急性调节蛋白（StAR）和类固醇17-α-羟化酶/17,20裂解酶（CYP17A1）的表达失调。我们的结果支持青春期接触THC可能通过直接和异常激活睾丸中的CBRs导致睾丸毒性。这些研究表明，青春期睾丸比成年睾丸对THC诱导的精子发生破坏更敏感。
