Early life stage transient aristolochic acid exposure induces behavioral hyperactivity but not nephrotoxicity in larval zebrafish

• Published in: Aquatic toxicology Vol. 238; p. 105916
• Main Authors: Chen, Jiangfei, Kong, Aijun, Shelton, Delia, Dong, Haojia, Li, Jiani, Zhao, Fan, Bai, Chenglian, Huang, Kaiyu, Mo, Wen, Chen, Shan, Xu, Hui, Tanguay, Robyn L, Dong, Qiaoxiang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2021
• Subjects: Aristolochic acids; Motor neuron; Neurobehavioral toxicity; Oxidative stress; Vision; Oxidative stress; Aristolochic acids; Motor neuron; Vision; Neurobehavioral toxicity
• ISSN: 0166-445X; 1879-1514; 1879-1514
• DOI: 10.1016/j.aquatox.2021.105916

•AA exposure at 8–24hpf induces hyperactivity, but not nephrotoxicity.•AA exposure results in aberrant motor neuron overgrowth.•AA exposure alters ocular development.•Oxidative stress and cell apoptosis may trigger AA's neurobehavioral effects. 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.