Yılmaztürk Derya, Alat Ömercan, Aksakal Özkan, Kullebi Berşan, Lafzi Ayşe, Şişman Turgay
Department of Molecular Biology and Genetics, Science Faculty, Atatürk University, 25240, Erzurum, Türkiye.
Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, 25240, Erzurum, Türkiye.
Food Chem Toxicol. 2025 Nov;205:115712. doi: 10.1016/j.fct.2025.115712. Epub 2025 Aug 23.
Synthetic cannabinoids like CUMYL-4CN-BINACA are emerging psychoactive substances with largely unknown developmental toxicity. Given the growing concern about prenatal and early-life exposure, this study assessed its impact on zebrafish embryos, focusing on morphological development, larval behavior, and gene expression. Embryos were exposed to concentrations of 1.25-40.0 mg/L during short-term (3-24 hpf) and long-term (3-120 hpf) windows. Key developmental endpoints, including survival, heartbeat, hatching, and locomotor activity, were evaluated. Molecular analyses were performed using qPCR to assess the expression of 19 genes related to apoptosis, behavior, and neurotransmission. Short-term exposure did not produce significant morphological changes, while long-term exposure resulted in concentration-dependent teratogenic effects such as pericardial and yolk sac edema, axial deformities, and hypoactivity. The LC and EC at 120 hpf were calculated as 16.624 mg/L and 9.083 mg/L, respectively. Gene expression analysis revealed significant alterations in behavioral genes (gnrh3, gnrhr3, kiss2), apoptotic markers (casp3a, casp8, ifng1, tp53), and the DNA repair gene rad51. Neurotransmission-related genes in dopaminergic (dat, drd1, drd3), serotonergic (5ht1aa, 5ht1a, 5ht1b, 5ht2c), and GABAergic (gabra1, gat1, abat, gad1b) systems were also dysregulated. These findings highlight the developmental and neurotoxic potential of CUMYL-4CN-BINACA, underlining the need for further toxicological risk assessments in early vertebrate models.
像CUMYL-4CN-BINACA这样的合成大麻素是新兴的精神活性物质，其发育毒性在很大程度上未知。鉴于对产前和生命早期接触的担忧日益增加，本研究评估了其对斑马鱼胚胎的影响，重点关注形态发育、幼体行为和基因表达。在短期（3-24小时胚胎期）和长期（3-120小时胚胎期）窗口内，将胚胎暴露于1.25-40.0毫克/升的浓度下。评估了包括存活、心跳、孵化和运动活动在内的关键发育终点。使用qPCR进行分子分析，以评估与细胞凋亡、行为和神经传递相关的19个基因的表达。短期暴露未产生明显的形态变化，而长期暴露则导致浓度依赖性致畸效应，如心包和卵黄囊水肿、轴向畸形和活动减退。120小时胚胎期的致死浓度（LC）和效应浓度（EC）分别计算为16.624毫克/升和9.083毫克/升。基因表达分析显示，行为基因（gnrh3、gnrhr3、kiss2）、凋亡标志物（casp3a、casp8、ifng1、tp53）和DNA修复基因rad51有显著改变。多巴胺能（dat、drd1、drd3）、5-羟色胺能（5ht1aa、5ht1a、5ht1b、5ht2c）和γ-氨基丁酸能（gabra1、gat1、abat、gad1b）系统中与神经传递相关的基因也失调。这些发现突出了CUMYL-4CN-BINACA的发育和神经毒性潜力，强调了在早期脊椎动物模型中进行进一步毒理学风险评估的必要性。
