State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, Nanjing 210008, China.
State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha 410081, China.
Int J Environ Res Public Health. 2020 Nov 29;17(23):8882. doi: 10.3390/ijerph17238882.
Concerns regarding environmental exposures and the impacts of pharmaceuticals on non-target aquatic organisms continue to increase. The antiepileptic drug carbamazepine (CBZ) is often detected as an aquatic contaminant and can disrupt various behaviors of fishes. However, there are few reports which investigate the mechanism of CBZ action in fish. The aim of the current study was to evaluate the effects of CBZ on embryonic development (i.e., hatching rate, heart rate, and body length) and early spontaneous movement. Moreover, we sought to investigate potential mechanisms by focusing on the gamma-aminobutyric acid (GABA) neurotransmitter system in zebrafish 6 days after of exposure. The results show that CBZ exposure did not cause significant effects on embryo development (hatching rate, heart rate, nor body length) at the test concentrations. However, the early spontaneous movement of embryos was inhibited following 10 μg/L CBZ exposure at 28-29 h post-fertilization (hpf). In addition, acetylcholinesterase (AChE) activity and GABA concentrations were increased with exposure, whereas glutamate (Glu) concentrations were decreased in larval zebrafish. Gene expression analysis revealed that GABA and glutamate metabolic pathways in zebrafish larvae were altered following exposure to CBZ. GABA transaminase () and glutamic acid decarboxylase () decreased to 100 µg/L, and glutamate receptor, ionotropic, N-methyl D-aspartate 1b () as well as the glutamate receptor, ionotropic, α-amino-3hydroxy-5methylisoxazole-4propionic 2b () were down-regulated with exposure to 1 µg/L CBZ. Our study suggests that CBZ, which can act as an agonist of the GABA receptor in humans, can also induce alterations in the GABAergic system in fish. Overall, this study improves understanding of the neurotoxicity and behavioral toxicity of zebrafish exposed to CBZ and generates data to be used to understand mechanisms of action that may underlie antiepileptic drug exposures.
人们对环境暴露和药物对非靶标水生生物的影响的担忧持续增加。抗癫痫药物卡马西平（CBZ）经常被检测为水生污染物，并且可以破坏鱼类的各种行为。然而，很少有研究报告调查 CBZ 在鱼类中的作用机制。本研究的目的是评估 CBZ 对胚胎发育（即孵化率、心率和体长）和早期自发运动的影响。此外，我们试图通过关注暴露后 6 天的斑马鱼中的γ-氨基丁酸（GABA）神经递质系统来研究潜在的机制。结果表明，在测试浓度下，CBZ 暴露对胚胎发育（孵化率、心率和体长）没有显著影响。然而，在受精后 28-29 小时，10μg/L CBZ 暴露会抑制胚胎的早期自发运动。此外，乙酰胆碱酯酶（AChE）活性和 GABA 浓度随着暴露而增加，而谷氨酸（Glu）浓度在幼鱼中降低。基因表达分析表明，暴露于 CBZ 后，斑马鱼幼鱼的 GABA 和谷氨酸代谢途径发生改变。GABA 转氨酶（）和谷氨酸脱羧酶（）下降到 100μg/L，谷氨酸受体，离子型，N-甲基-D-天冬氨酸 1b（）以及谷氨酸受体，离子型，α-氨基-3-羟基-5-甲基异恶唑-4-丙酸 2b（）在暴露于 1μg/L CBZ 时下调。我们的研究表明，CBZ 可以作为人类 GABA 受体的激动剂，也可以诱导鱼类中 GABA 能系统的改变。总的来说，这项研究提高了对斑马鱼暴露于 CBZ 时的神经毒性和行为毒性的理解，并产生了用于理解可能作为抗癫痫药物暴露基础的作用机制的数据。
