Zhang Yi, Li Wenzheng, Zhu Jun, Qian Xin, Pei Wenlong, Gu Zhenyang, Wu Qian, Zhang Zhan, Li Lei
Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
Toxicol Appl Pharmacol. 2023 Nov 1;478:116708. doi: 10.1016/j.taap.2023.116708. Epub 2023 Sep 30.
Pentachlorophenol (PCP) is a ubiquitous environmental toxicant with various adverse effects. Although its neurotoxicity has been reported, the underlying mechanism and subsequent detoxification remain unclear. In this study, embryos and adult zebrafish were exposed to PCP to determine its potential neurotoxic mechanism and protective indicators. The survival rate, heart rate, mobility time, active status and moving distance were significantly decreased in larvae after 30 μg/L PCP exposure. Likewise, the mobile time, latency to the first movement, velocity and moving distance of adult zebrafish were significantly reduced by PCP exposure. Untargeted metabolomics analysis of larvae revealed that arginine and proline metabolism was the primary pathway affected by PCP exposure, reflected by increased proline and decreased citrulline (CIT) contents, which were confirmed by quantitative data. PCP exposure suppressed the conversion from arginine to CIT in larvae by downregulating the expression of nos1 and nos2a. Ornithine content was increased in the brains and intestines of adult zebrafish after PCP exposure, which inhibited ornithine catabolism to CIT by downregulating otc, resulting in reduced CIT. Intriguingly, CIT supplementation significantly restored the neurobehavioral defects induced by PCP in larvae and adult zebrafish. CIT supplementation upregulated the expression of ef1α and tuba1 in larvae and inhibited the downregulation of ef1α in the brains of adult zebrafish. Taken together, these results indicated that CIT supplementation could protect against PCP-induced neurotoxicity by upregulating the expression of genes involved in neuronal development and function.
五氯苯酚（PCP）是一种普遍存在的环境毒物，具有多种不良影响。尽管其神经毒性已有报道，但其潜在机制和后续解毒过程仍不清楚。在本研究中，将胚胎和成年斑马鱼暴露于PCP中，以确定其潜在的神经毒性机制和保护指标。暴露于30μg/L PCP后，幼虫的存活率、心率、游动时间、活动状态和游动距离显著降低。同样，成年斑马鱼的游动时间、首次运动潜伏期、速度和游动距离也因PCP暴露而显著减少。对幼虫进行非靶向代谢组学分析发现，精氨酸和脯氨酸代谢是受PCP暴露影响的主要途径，表现为脯氨酸增加和瓜氨酸（CIT）含量降低，定量数据证实了这一点。PCP暴露通过下调nos1和nos2a的表达抑制了幼虫中精氨酸向CIT的转化。PCP暴露后成年斑马鱼的大脑和肠道中鸟氨酸含量增加，通过下调otc抑制鸟氨酸分解代谢为CIT，导致CIT减少。有趣的是，补充CIT可显著恢复PCP诱导的幼虫和成年斑马鱼的神经行为缺陷。补充CIT上调了幼虫中ef1α和tuba1的表达，并抑制了成年斑马鱼大脑中ef1α的下调。综上所述，这些结果表明补充CIT可通过上调参与神经元发育和功能的基因表达来预防PCP诱导的神经毒性。
