Developmental Effects of Cannabidiol and Δ9-Tetrahydrocannabinol in Zebrafish
Developmental Effects of Cannabidiol and Δ9-Tetrahydrocannabinol in Zebrafish
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DOI：
10.1093/toxsci/kfx232
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发表时间：
2018-03-01
影响因子：
3.8
通讯作者：
Willett, Kristine L.
中科院分区：
文献类型：
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作者：
Carty, Dennis R.;Thornton, Cammi;Willett, Kristine L.
在过去的几年里，大麻二醇(CBD)因其在治疗耐药癫痫(如Dravet综合征)方面的潜力而受到广泛关注。虽然CBD在减少癫痫发作频率方面显示出坊间疗效，但关于CBD对生理、发育、器官发生或行为的潜在副作用知之甚少。该项目的目标是比较在发育过程中接触Delta(9)-四氢大麻酚(THC)或CBD后相对的形态、行为和基因表达表型。斑马鱼从囊胚期(受精后96h)暴露到0.3，0.6，1.25，2.5，5 mg/L(1，2，4，8，16亩M)或0.07，0.1，0.3，0.6，1.25 mg/L CBD(0.25，0.5，1，2，4亩M)。尽管胆总管和胆总管畸形有相似之处，如水肿症、中轴线弯曲、眼/鼻/颌/躯干/鳍畸形、膀胱扩张和行为异常，但胆总管的半数致死剂量(0.53 mg/L)比四氢呋喃(3.65 mg/L)低近7倍。在96hpF时，c-fos、DAZL和VasA在THC暴露后有差异表达，但CBD只显著增加c-fos的表达。尽管THC的水浓度较高，但与THC相比，大麻二酚具有更高的生物浓缩性。这项工作支持大麻素暴露对发育的潜在影响，但还需要更多的研究来评估潜在的影响及其毒性的分子机制。
Cannabidiol (CBD) has gained much attention in the past several years for its therapeutic potential in the treatment of drug-resistant epilepsy, such as Dravet syndrome. Although CBD has shown anecdotal efficacy in reducing seizure frequency, little is known regarding the potential adverse side effects of CBD on physiology, development, organogenesis, or behavior. The goal of this project was to compare the relative morphological, behavioral, and gene expression phenotypes resulting after a developmental exposure to Delta(9)-tetrahydrocannabinol (THC) or CBD. Zebrafish were exposed from blastula through larval stage (96h postfertilization [hpf]) to 0.3, 0.6, 1.25, 2.5, 5 mg/l (1, 2, 4, 8, 16 mu M) THC or 0.07, 0.1, 0.3, 0.6, 1.25 mg/l CBD (0.25, 0.5, 1, 2, 4 mu M). Despite the similarity in THC and CBD dysmorphologies, ie, edemas, curved axis, eye/snout/jaw/trunk/fin deformities, swim bladder distention, and behavioral abnormalities, the LC50 for CBD (0.53 mg/l) was nearly 7 times lower than THC (3.65 mg/l). At 96 hpf, c-fos, dazl, and vasa were differentially expressed following THC exposure, but only c-fos expression was significantly increased by CBD. Cannabidiol was more bioconcentrated compared with THC despite higher THC water concentrations. This work supports the potential for persistent developmental impacts of cannabinoid exposure, but more studies are needed to assess latent effects and their molecular mechanisms of toxicity.