Cannabis use has been increasing worldwide for recreational and medical purposes. Consumption by pregnant women is associated with disturbances in pregnancy outcome, such as low birth weight, prematurity and intrauterine growth retardation, though the underlying biochemical mechanisms are unknown. The endocannabinoid system is involved in several reproductive events and the disruption of its homeostasis by ∆⁹-tetrahydrocannabinol (THC), the main psychoactive cannabinoid, may lead to a negative gestational outcome. In human placenta, THC impairs the levels of the endocannabinoid anandamide (AEA). The other major endocannabinoid, 2-arachidonoylglycerol (2-AG) also plays an important role on proper placentation and pregnancy success. However, THC impact on 2-AG homeostasis has never been addressed. Hence, the effects of THC in 2-AG levels and metabolic enzymes expression were explored. Long-term treatment impairs the expression of the main 2-AG synthetic and degradative enzymes. Curiously, with the highest concentration, despite the maintenance of diacylglycerol lipase alpha (DAGLα) and the decrease in monoacylglycerol lipase (MAGL) expression, 2-AG levels remain constant. Given the endocannabinoid signalling local tight regulation, we hypothesize the involvement of other 2-AG degradative enzymes. Indeed, THC increases the expression of the hydrolyzing enzymes alpha beta hydrolase domain-6 (ABHD6) and -12 (ABHD12), that we firstly describe in human placental tissues. The results show that THC, depending on time of exposure, induces alterations in 2-AG metabolic enzymes expression in placental explants, highlighting the importance of 2-AG regulation and endocannabinoid signalling in placental development. Alterations in this homeostasis may explain the negative pregnancy outcome related to cannabis consumption.

在全世界，出于娱乐和医疗目的，大麻的使用量一直在增加。尽管基本的生化机制尚不清楚，但孕妇的摄入与妊娠结局有关，例如低出生体重，早产和宫内发育迟缓。内源性大麻素系统参与多种生殖活动及其动态平衡由Δ中断⁹主要精神活性大麻素-四氢大麻酚（THC）可能导致妊娠结果阴性。在人胎盘中，四氢大麻酚会破坏内源性大麻素七叶酰胺（AEA）的水平。其他主要的内源性大麻素2-花生四烯酸甘油酯（2-AG）在正确的胎盘形成和妊娠成功中也起着重要作用。但是，THC对2-AG稳态的影响从未得到解决。因此，探讨了THC在2-AG水平和代谢酶表达中的作用。长期治疗会损害主要的2-AG合成和降解酶的表达。奇怪的是，尽管浓度最高，尽管维持了二酰基甘油脂肪酶α（DAGLα）和单酰基甘油脂肪酶（MAGL）表达下降，但是2-AG的水平仍然保持不变。考虑到内源性大麻素信号表明局部严格调节，我们假设其他2-AG降解酶的参与。实际上，四氢大麻酚增加了我们首先在人胎盘组织中描述的水解酶αβ水解酶结构域6（ABHD6）和-12（ABHD12）的表达。结果表明，THC取决于暴露时间，可诱导胎盘外植体中2-AG代谢酶表达的改变，突显了2-AG调节和内源性大麻素信号在胎盘发育中的重要性。这种动态平衡的改变可能解释了与大麻消费有关的不良妊娠结局。根据暴露时间，诱导胎盘外植体中2-AG代谢酶表达的改变，突出了2-AG调节和内源性大麻素信号在胎盘发育中的重要性。这种动态平衡的改变可能解释了与大麻消费有关的不良妊娠结局。根据暴露时间，诱导胎盘外植体中2-AG代谢酶表达的改变，突出了2-AG调节和内源性大麻素信号在胎盘发育中的重要性。这种动态平衡的改变可能解释了与大麻消费有关的不良妊娠结局。