Omics techniques reveal the toxicity mechanisms of three antiepileptic drugs to juvenile zebrafish (Danio rerio) brain and liver

Huiting Yang; Xiaohong Gu; Huihui Chen; Qingfei Zeng; Zhigang Mao; You Ge

doi:10.1016/j.aquatox.2023.106668

Omics techniques reveal the toxicity mechanisms of three antiepileptic drugs to juvenile zebrafish (Danio rerio) brain and liver

Aquat Toxicol. 2023 Sep:262:106668. doi: 10.1016/j.aquatox.2023.106668. Epub 2023 Aug 23.

Authors

Huiting Yang¹, Xiaohong Gu², Huihui Chen³, Qingfei Zeng³, Zhigang Mao³, You Ge¹

Affiliations

¹ State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, Nanjing 210008, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, Nanjing 210008, China. Electronic address: xhgu@niglas.ac.cn.
³ State Key Laboratory of Lake Science and Environment, Nanjing Institute of Geography and Limnology, Chinese Academy of Sciences, Nanjing 210008, China.

PMID: 37659109
DOI: 10.1016/j.aquatox.2023.106668

Abstract

Epilepsy, a neurological disorder, is characterized by seizures that are an appearance of excessive brain activity and is symptomatically treated with antiepileptic drugs (AEDs). Oxcarbazepine (OCBZ), lamotrigine (LTG), and carbamazepine (CBZ) are widely used AEDs in clinics and are very often detected in aquatic environments. However, neither the sub-lethal effects nor the specific mechanisms of these AEDs' action on the fish are well understood. In this study, juvenile zebrafish were exposed to a sub-lethal concentration (100 μg/L) of OCBZ, LTG, and CBZ for 28 d, after which indicators of oxidative stress (i.e. superoxide dismutase (SOD) activity, catalase (CAT) activity, and malondialdehyde (MDA) level) and neurotoxicity (i.e. acetylcholinesterase (AChE) activity, γ-aminobutyric acid (GABA) level, and glutamic acid (Glu) level) were measured. Brain SOD activity was significantly increased by three AEDs, while brain CAT activity was significantly inhibited by LTG and CBZ. Liver SOD activity was significantly enhanced by CBZ, and liver CAT activity was significantly induced by OCBZ and LTG. Liver MDA level was significantly increased by three AEDs. Brain AChE activity was significantly increased by LTG and CBZ, and brain GABA level was significantly enhanced by three AEDs. However, there were no significant alterations in the levels of MDA and Glu in zebrafish brain. To ascertain mechanisms of AEDs-induced toxicity, brain transcriptomics and liver metabolomics were conducted in zebrafish. The brain transcriptomics results showed that lots of differentially expressed genes (DEGs) were enriched in the sensory system, the immune system, the digestive system, the metabolic processes, and others in three AEDs treated groups. The metabolomics data indicated dysregulation of glycerophospholipid signaling and lipid homeostasis in zebrafish liver after three AEDs exposure. The overall results of this study improve understanding of the sub-lethal effects and potential molecular mechanisms of action of AEDs in fish.

Keywords: Antiepileptic drugs; Metabolomics; Neurotoxicity; Oxidative stress; Transcriptomes.

MeSH terms

Acetylcholinesterase
Animals
Anticonvulsants* / toxicity
Brain
Carbamazepine / toxicity
Glutamic Acid
Liver
Superoxide Dismutase
Water Pollutants, Chemical* / toxicity
Zebrafish

Substances

Anticonvulsants
Acetylcholinesterase
Water Pollutants, Chemical
Carbamazepine
Glutamic Acid
Superoxide Dismutase