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

IF 3.4 3区 医学 Q2 TOXICOLOGY
Jinhwan Lim, Caitlin Quach, Julie Nguyen, Andrew Rizk, Samantha Getze, Kwang-Mook Jung, Stephen V Mahler, Daniele Piomelli, Ulrike Luderer
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Abstract

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.

青少年接触Δ9-tetrahydrocannabinol (THC)会损害年轻成年雄性小鼠的睾丸功能。
大麻的使用通常始于青春期的早期到中期。Δ9-tetrahydrocannabinol (THC)是大麻的主要精神活性成分,以大麻素受体(CBRs)为靶点发挥其药理作用。在人类和啮齿类动物的睾丸中已经观察到CBRs的表达,但它们在控制生殖功能方面的潜在作用尚不清楚。我们的目的是阐明四氢大麻酚暴露在青春期或青年成年期如何影响男性生殖健康。从出生后第30天(PND)至第43天(青春期暴露)或第70天至第83天(成年暴露),C57BL/6N雄性小鼠每天1次腹腔注射四氢大麻酚(5 mg/kg)或对照物,分别在第70天和第110天收获睾丸。结果表明,小鼠睾丸中分别表达了cbr (CB1R和CB2R)和生物合成或灭活内源性大麻素anandamide (AEA)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)。青少年时期的四氢大麻酚暴露降低了青年睾丸的精子数量,增加了精管变性,而成年时期的四氢大麻酚暴露对精子发生和精管形态没有影响。青少年和成人四氢大麻酚暴露均导致血浆睾酮水平下降;然而,只有青春期四氢大麻酚暴露的小鼠出现类固醇生成受损,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)表达异常。我们的研究结果支持青少年THC暴露可能通过睾丸中cbr的直接和异常激活引起睾丸毒性。这些研究表明,青少年睾丸比成人睾丸对四氢大麻酚诱导的精子发生破坏更敏感。
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来源期刊
Toxicological Sciences
Toxicological Sciences 医学-毒理学
CiteScore
7.70
自引率
7.90%
发文量
118
审稿时长
1.5 months
期刊介绍: The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology. The primary focus of Toxicological Sciences is on original research articles. The journal also provides expert insight via contemporary and systematic reviews, as well as forum articles and editorial content that addresses important topics in the field. The scope of Toxicological Sciences is focused on a broad spectrum of impactful toxicological research that will advance the multidisciplinary field of toxicology ranging from basic research to model development and application, and decision making. Submissions will include diverse technologies and approaches including, but not limited to: bioinformatics and computational biology, biochemistry, exposure science, histopathology, mass spectrometry, molecular biology, population-based sciences, tissue and cell-based systems, and whole-animal studies. Integrative approaches that combine realistic exposure scenarios with impactful analyses that move the field forward are encouraged.
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