Aristolochic acids (AA) are nitrophenanthrene carboxylic acids found in plants of the Aristolochiaceae family. Humans are exposed to AA by deliberately taking herbal medicines or unintentionally as a result of environmental contamination. AA is notorious for its nephrotoxicity, however, fewer studies explore potential neurotoxicity associated with AA exposure. The developing nervous system is vulnerable to xenobiotics, and pregnant women exposed to AA may put their fetuses at risk. In the present study, we used the embryonic zebrafish model to evaluate the developmental neurotoxicity associated with AA exposure. At non-teratogenic concentrations (≤ 4 µM), continuous AA exposure from 8 to 120 hours post fertilization (hpf) resulted in larval hyperactivity that was characterized by increased moving distance, elevated activity and faster swimming speeds in several behavioral assays. Further analysis revealed that 8–24 hpf is the most sensitive exposure window for AA-induced hyperactivity. AA exposures specifically increased motor neuron proliferation, increased apoptosis in the eye, and resulted in cellular oxidative stress. In addition, AA exposures increased larval eye size and perturbed the expression of vision genes. Our study, for the first time, demonstrates that AA is neurotoxic to the developmental zebrafish with a sensitive window distinct from its well-documented nephrotoxicity.

马兜铃酸 (AA) 是在马兜铃科植物中发现的硝基菲羧酸家庭。人类通过故意服用草药或由于环境污染而无意中暴露于 AA。AA 因其肾毒性而臭名昭著，然而，探索与 AA 暴露相关的潜在神经毒性的研究较少。发育中的神经系统很容易受到异生素的影响，接触 AA 的孕妇可能会使胎儿处于危险之中。在本研究中，我们使用胚胎斑马鱼模型来评估与 AA 暴露相关的发育神经毒性。在非致畸浓度（≤ 4 µM）下，受精后 8 至 120 小时连续暴露于 AA 导致幼虫过度活跃，其特征是在几种行为测定中移动距离增加、活动增加和游泳速度加快。进一步分析表明，8-24 hpf 是 AA 诱发的多动症最敏感的暴露窗口。AA 暴露特别会增加运动神经元增殖，增加眼睛细胞凋亡，并导致细胞氧化应激。此外，AA 暴露增加了幼虫眼睛的大小并扰乱了视觉基因的表达。我们的研究首次证明 AA 对发育中的斑马鱼具有神经毒性，其敏感窗口不同于其有据可查的肾毒性。