Abstract：
Cannabidiol (CBD) is a non-psychoactive component of cannabis with potential applications in biomedicine, food, and cosmetics due to its analgesic, anti-inflammatory, and anticonvulsant properties. However, increasing reports of adverse CBD exposure events underscore the necessity of evaluating its toxicity. In this study, we investigated the developmental toxicity of CBD in zebrafish during the embryonic (0-4 dpf, days post fertilization) and early larval stages (5-7 dpf). The median lethal concentration of CBD in embryos/larvae is 793.28 μg/L. CBD exhibited concentration-dependent manner (ranging from 250 to 1500 μg/L) in inducing serious malformed somatotypes, like shorter body length, pericardial cysts, vitelline cysts, spinal curvature, and smaller eyes. However, no singular deformity predominates. The 5-month-old zebrafish treated with 100 and 200 μg/L of CBD during the embryonic and early larval stages produced fewer offspring with higher natural mortality and malformation rate. Gonadal growth and gamete development were inhibited. Transcriptomic and metabolomic analyses conducted with 400 μg/L CBD on embryos/larvae from 0 to 5 dpf suggested that CBD promoted the formation and transportation of extracellular matrix components on 1 dpf, promoting abnormal cell division and migration, probably resulting in random malformed somatotypes. It inhibited optical vesicle development and photoreceptors formation on 2 and 3 dpf, resulting in damaged sight and smaller eye size. CBD also induced an integrated stress response on 4 and 5 dpf, disrupting redox, protein, and cholesterol homeostasis, contributing to cellular damage, physiological dysfunction, embryonic death, and inhibited reproductive system and ability in adult zebrafish. At the tested concentrations, CBD exhibited developmental toxicity, lethal toxicity, and reproductive inhibition in zebrafish. These findings demonstrate that CBD threatens the model aquatic animal, highlighting the need for additional toxicological evaluations of CBD before its inclusion in dietary supplements, edible food, and other products.
摘要：
大麻二酚（CBD）是大麻的非精神活性成分，在生物医学中具有潜在应用，食物,和化妆品由于它的镇痛，抗炎,和抗惊厥特性。然而,越来越多的CBD不良暴露事件的报告强调了评估其毒性的必要性.在这项研究中,我们调查了CBD在斑马鱼胚胎期间的发育毒性(0-4dpf，受精后几天）和幼虫早期阶段（5-7dpf）。胚胎/幼虫中CBD的中位致死浓度为793.28μg/L。CBD在诱导严重畸形的体型时表现出浓度依赖性方式（范围从250到1500μg/L），像较短的身体长度，心包囊肿,卵黄囊肿,脊柱弯曲，更小的眼睛。然而,没有奇异的畸形占主导地位。在胚胎期和幼虫早期用100和200μg/LCBD处理的5个月大斑马鱼产生的后代较少，自然死亡率和畸形率较高。性腺生长和配子发育受到抑制。用400μg/LCBD对0至5dpf的胚胎/幼虫进行的转录组和代谢组学分析表明，CBD促进了1dpf上胞外基质成分的形成和运输，促进异常细胞分裂和迁移，可能导致随机畸形的体型。它在2和3dpf上抑制光学囊泡的发育和光感受器的形成，导致视力受损和眼睛尺寸变小。CBD还诱导了4和5dpf的综合应激反应，破坏氧化还原，蛋白质，和胆固醇稳态，导致细胞损伤，生理机能障碍,胚胎死亡,并抑制成年斑马鱼的生殖系统和能力。在测试浓度下，CBD表现出发育毒性，致死毒性，和斑马鱼的生殖抑制。这些发现表明，CBD威胁模式水生动物，强调在将CBD纳入膳食补充剂之前需要对其进行额外的毒理学评估，食用食品,和其他产品。
