PMID- 33280847 OWN - NLM STAT- MEDLINE DCOM- 20210101 LR - 20210101 IS - 1879-1298 (Electronic) IS - 0045-6535 (Linking) VI - 265 DP - 2021 Feb TI - Involvement of dopamine signaling pathway in neurodevelopmental toxicity induced by isoniazid in zebrafish. PG - 129109 LID - S0045-6535(20)33306-3 [pii] LID - 10.1016/j.chemosphere.2020.129109 [doi] AB - AIMS: This study evaluated the neurodevelopmental toxicity of isoniazid (INH) in zebrafish embryos and the underlying mechanism. METHODS: Zebrafish embryos were exposed to different concentrations (2 mM, 4 mM, 8 mM, 16 mM, 32 mM) INH for 120 hpf. During the exposure period, the percentage of embryo/larva mortality, hatching, and morphological malformation were checked every 24 h until 120 hpf. The development of blood vessels in the brain was observed at 72 hpf and 120 hpf, and behavioral capacity and acridine orange (AO) staining were measured at 120 hpf. Alterations in the mRNA expression of apoptosis and dopamine signaling pathway related genes were assessed by real-time quantitative PCR (qPCR). RESULTS: INH considerably inhibited zebrafish embryo hatching and caused zebrafish larval malformation (such as brain malformation, delayed yolk sac absorption, spinal curvature, pericardial edema, and swim bladder defects). High concentration of INH (16 mM, 32 mM) even induced death of zebrafish. In addition, INH exposure markedly restrained the ability of the zebrafish autonomous movement, shortened the length of dopamine neurons and inhibited vascular development in the brain. No obvious apoptotic cells were observed in the control group, whereas considerable numbers of apoptotic cells appeared in the head of INH-treated larvae at 120 hpf. PCR results indicated that INH significantly raised the transcription levels of caspase-3, -8, -9, and bax and significantly decreased bcl-2 and bcl-2/bax in the zebrafish apoptotic signaling pathway. INH also markedly decreased the genes related to dopamine signaling pathway (th1, dat, drd1, drd2a, drd3, and drd4b). CONCLUSIONS: Experimental results indicated that INH had obvious neurodevelopmental toxicity in zebrafish. Persistent exposure to INH for 120 h caused apoptosis, decreased dopaminergic gene expression, altered vasculature, and reduced behaviors. CI - Copyright (c) 2020 Elsevier Ltd. All rights reserved. FAU - Liu, Li AU - Liu L AD - School of Pharmacy, Changzhou University, Changzhou, Jiangsu Province, PR China. FAU - Wu, Fang-Yan AU - Wu FY AD - School of Pharmacy, Changzhou University, Changzhou, Jiangsu Province, PR China; Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, PR China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, Shandong Province, PR China. FAU - Zhu, Cheng-Yue AU - Zhu CY AD - Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, PR China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, Shandong Province, PR China. FAU - Zou, Hong-Yuan AU - Zou HY AD - Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, PR China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, Shandong Province, PR China. FAU - Kong, Rui-Qi AU - Kong RQ AD - Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, PR China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, Shandong Province, PR China. FAU - Ma, Yu-Kui AU - Ma YK AD - Shandong Academy of Pharmaceutical Sciences, Jinan, Shandong Province, PR China. FAU - Su, Dan AU - Su D AD - Department of Pharmacy, Changzhou No.2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, PR China. FAU - Song, Guo-Qiang AU - Song GQ AD - School of Pharmacy, Changzhou University, Changzhou, Jiangsu Province, PR China. FAU - Zhang, Yun AU - Zhang Y AD - Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, PR China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, Shandong Province, PR China. Electronic address: zhangyun@sdas.org. FAU - Liu, Ke-Chun AU - Liu KC AD - Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, PR China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Jinan, Shandong Province, PR China. Electronic address: hliukch@sdas.org. LA - eng PT - Journal Article DEP - 20201128 PL - England TA - Chemosphere JT - Chemosphere JID - 0320657 RN - V83O1VOZ8L (Isoniazid) RN - VTD58H1Z2X (Dopamine) SB - IM MH - Animals MH - Dopamine MH - *Embryo, Nonmammalian MH - Isoniazid/toxicity MH - Larva MH - Signal Transduction MH - *Zebrafish/genetics OTO - NOTNLM OT - Apoptosis OT - Dopamine signaling pathway OT - Isoniazid OT - Neurodevelopmental toxicity OT - Zebrafish COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/12/08 06:00 MHDA- 2021/01/02 06:00 CRDT- 2020/12/07 05:26 PHST- 2020/08/31 00:00 [received] PHST- 2020/11/02 00:00 [revised] PHST- 2020/11/22 00:00 [accepted] PHST- 2020/12/08 06:00 [pubmed] PHST- 2021/01/02 06:00 [medline] PHST- 2020/12/07 05:26 [entrez] AID - S0045-6535(20)33306-3 [pii] AID - 10.1016/j.chemosphere.2020.129109 [doi] PST - ppublish SO - Chemosphere. 2021 Feb;265:129109. doi: 10.1016/j.chemosphere.2020.129109. Epub 2020 Nov 28.