Chromium induced neurotoxicity by altering metabolism in zebrafish larvae

Background: Recently, both trivalent chromium Cr (III) and hexavalent chromium Cr (VI) have been reported to produce neurotoxicity. However, the underlying mechanisms of the neurotoxicity caused by different chemical valence of chromium remain unclear. Objective: The purpose of this study was to inv...

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Autores principales:	Yawen Xu, Li Wang, Jun Zhu, Ping Jiang, Zhan Zhang, Lei Li, Qian Wu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Chromium Neurotoxicity Metabolism One carbon metabolism DNA methylation Histone methylation Environmental pollution TD172-193.5 Environmental sciences GE1-350
Acceso en línea:	https://doaj.org/article/df668b3ef8954ef68342d61674392cd1
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id	oai:doaj.org-article:df668b3ef8954ef68342d61674392cd1
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Chromium Neurotoxicity Metabolism One carbon metabolism DNA methylation Histone methylation Environmental pollution TD172-193.5 Environmental sciences GE1-350
spellingShingle	Chromium Neurotoxicity Metabolism One carbon metabolism DNA methylation Histone methylation Environmental pollution TD172-193.5 Environmental sciences GE1-350 Yawen Xu Li Wang Jun Zhu Ping Jiang Zhan Zhang Lei Li Qian Wu Chromium induced neurotoxicity by altering metabolism in zebrafish larvae
description	Background: Recently, both trivalent chromium Cr (III) and hexavalent chromium Cr (VI) have been reported to produce neurotoxicity. However, the underlying mechanisms of the neurotoxicity caused by different chemical valence of chromium remain unclear. Objective: The purpose of this study was to investigate the mechanism of neurotoxicity induced by exposure to chromium with different valence states based on metabolic disturbance in zebrafish larvae. Methods: Zebrafish embryos were exposed to 1 mg/L Cr (III) and 1 mg/L Cr (VI) for 120 hpf respectively. The related indexes of neural development were observed by stereoscope and behavior analysis system. 8OH-dG were detected using enzyme-linked immunosorbent assay. The generation of reactive oxygen species was detected using an oxidant-sensing probe 2',7'-dichlorodihydrofluorescein diacetate. AChE activity was determined by a colorimetric assay based on hydrolysis of acetylcholine. The expression levels of neurodevelopmental genes and methyltransferase genes in juvenile zebrafish was analyzed by real-time PCR. The methylation status of neurogenin1 and neurod1 genes was detected by bisulfite sequencing PCR. The binding of H3K27me3 was detected by chromatin immunoprecipitation-qPCR. Metabolic profiles and one carbon metabolic analysis were performed by UPLC-MS. Results: There were no significant differences in survival rate, hatching rate and spontaneous movement of zebrafish in both Cr-exposed groups compared to the control. The malformation rate in Cr (VI) -exposed group was obviously increased compared to the control and Cr (III) -exposed group. At 48hpf and 72hpf of exposure, the embryonic heart rate in Cr (III)-exposed group was significantly higher than that of Cr (VI)-exposed group and the control. At 120hpf, zebrafish in both Cr-exposed groups exhibited decreasing changes in swimming distance and disturbance of sensitivity to light and dark. 8OH-dG in Cr (VI)-exposed group were significantly higher than that in the control. The generation of ROS in both Cr -exposed groups was significantly higher than that in the control. The activity of AchE was significantly decreased in both Cr-exposed groups compared to the control. Most of early neurogenesis related genes, such as α-tubulin, elavl3, gap43, sox19b, neurogenin1 and neurod1 in Cr-exposed groups were significantly up-regulated compared to those in the control. The expression of dnmt1 and dnmt3 genes was significantly down-regulated in both Cr-exposed groups. BSP-PCR results showed that genic sequences in the neurogenin1 and neurod1 genes have lower levels of DNA methylation in both Cr-exposed groups, especial in Cr (VI)-exposed group. ChIP analysis showed that there was a decrease in H3K27me3 binding within the corresponding region of neurogenin1 in both Cr-exposed groups and that of neurod1 in Cr (III)-exposed group. Untargeted metabolomic analysis showed that significant changes in metabolites induced by Cr exposure were associated with differences in primary bile acid biosynthesis, phospholipid biosynthesis (phosphatidylcholine biosynthesis and phosphatidylethanolamine biosynthesis), linoleic acid metabolism, arachidonic acid metabolism, amino acid metabolism, purine metabolism, betaine metabolism, spermidine and spermine biosynthesis, and folate metabolism, the last four of which are related to one carbon metabolism. Targeted analysis of one carbon metabolites (5-MT, Gly, Met, SAH and Hcy) related with folate cycle and methionine metabolism were significantly decreased upon Cr exposure. The elevated SAM to SAH ratio in both Cr- exposed group indicated the decreasing capacity for methylation reaction. Conclusion: Cr (III) and Cr (VI) can induce neurotoxicity by interfering with one carbon metabolism and affecting DNA methylation and histone methylation to regulate the expression of neuro-related genes. Cr exposure also influenced primary bile acid biosynthesis and phospholipid biosynthesis, which are associated with neuroprotective effects and need to be further validated.
format	article
author	Yawen Xu Li Wang Jun Zhu Ping Jiang Zhan Zhang Lei Li Qian Wu
author_facet	Yawen Xu Li Wang Jun Zhu Ping Jiang Zhan Zhang Lei Li Qian Wu
author_sort	Yawen Xu
title	Chromium induced neurotoxicity by altering metabolism in zebrafish larvae
title_short	Chromium induced neurotoxicity by altering metabolism in zebrafish larvae
title_full	Chromium induced neurotoxicity by altering metabolism in zebrafish larvae
title_fullStr	Chromium induced neurotoxicity by altering metabolism in zebrafish larvae
title_full_unstemmed	Chromium induced neurotoxicity by altering metabolism in zebrafish larvae
title_sort	chromium induced neurotoxicity by altering metabolism in zebrafish larvae
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/df668b3ef8954ef68342d61674392cd1
work_keys_str_mv	AT yawenxu chromiuminducedneurotoxicitybyalteringmetabolisminzebrafishlarvae AT liwang chromiuminducedneurotoxicitybyalteringmetabolisminzebrafishlarvae AT junzhu chromiuminducedneurotoxicitybyalteringmetabolisminzebrafishlarvae AT pingjiang chromiuminducedneurotoxicitybyalteringmetabolisminzebrafishlarvae AT zhanzhang chromiuminducedneurotoxicitybyalteringmetabolisminzebrafishlarvae AT leili chromiuminducedneurotoxicitybyalteringmetabolisminzebrafishlarvae AT qianwu chromiuminducedneurotoxicitybyalteringmetabolisminzebrafishlarvae
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spelling	oai:doaj.org-article:df668b3ef8954ef68342d61674392cd12021-11-14T04:28:24ZChromium induced neurotoxicity by altering metabolism in zebrafish larvae0147-651310.1016/j.ecoenv.2021.112983https://doaj.org/article/df668b3ef8954ef68342d61674392cd12021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0147651321010952https://doaj.org/toc/0147-6513Background: Recently, both trivalent chromium Cr (III) and hexavalent chromium Cr (VI) have been reported to produce neurotoxicity. However, the underlying mechanisms of the neurotoxicity caused by different chemical valence of chromium remain unclear. Objective: The purpose of this study was to investigate the mechanism of neurotoxicity induced by exposure to chromium with different valence states based on metabolic disturbance in zebrafish larvae. Methods: Zebrafish embryos were exposed to 1 mg/L Cr (III) and 1 mg/L Cr (VI) for 120 hpf respectively. The related indexes of neural development were observed by stereoscope and behavior analysis system. 8OH-dG were detected using enzyme-linked immunosorbent assay. The generation of reactive oxygen species was detected using an oxidant-sensing probe 2',7'-dichlorodihydrofluorescein diacetate. AChE activity was determined by a colorimetric assay based on hydrolysis of acetylcholine. The expression levels of neurodevelopmental genes and methyltransferase genes in juvenile zebrafish was analyzed by real-time PCR. The methylation status of neurogenin1 and neurod1 genes was detected by bisulfite sequencing PCR. The binding of H3K27me3 was detected by chromatin immunoprecipitation-qPCR. Metabolic profiles and one carbon metabolic analysis were performed by UPLC-MS. Results: There were no significant differences in survival rate, hatching rate and spontaneous movement of zebrafish in both Cr-exposed groups compared to the control. The malformation rate in Cr (VI) -exposed group was obviously increased compared to the control and Cr (III) -exposed group. At 48hpf and 72hpf of exposure, the embryonic heart rate in Cr (III)-exposed group was significantly higher than that of Cr (VI)-exposed group and the control. At 120hpf, zebrafish in both Cr-exposed groups exhibited decreasing changes in swimming distance and disturbance of sensitivity to light and dark. 8OH-dG in Cr (VI)-exposed group were significantly higher than that in the control. The generation of ROS in both Cr -exposed groups was significantly higher than that in the control. The activity of AchE was significantly decreased in both Cr-exposed groups compared to the control. Most of early neurogenesis related genes, such as α-tubulin, elavl3, gap43, sox19b, neurogenin1 and neurod1 in Cr-exposed groups were significantly up-regulated compared to those in the control. The expression of dnmt1 and dnmt3 genes was significantly down-regulated in both Cr-exposed groups. BSP-PCR results showed that genic sequences in the neurogenin1 and neurod1 genes have lower levels of DNA methylation in both Cr-exposed groups, especial in Cr (VI)-exposed group. ChIP analysis showed that there was a decrease in H3K27me3 binding within the corresponding region of neurogenin1 in both Cr-exposed groups and that of neurod1 in Cr (III)-exposed group. Untargeted metabolomic analysis showed that significant changes in metabolites induced by Cr exposure were associated with differences in primary bile acid biosynthesis, phospholipid biosynthesis (phosphatidylcholine biosynthesis and phosphatidylethanolamine biosynthesis), linoleic acid metabolism, arachidonic acid metabolism, amino acid metabolism, purine metabolism, betaine metabolism, spermidine and spermine biosynthesis, and folate metabolism, the last four of which are related to one carbon metabolism. Targeted analysis of one carbon metabolites (5-MT, Gly, Met, SAH and Hcy) related with folate cycle and methionine metabolism were significantly decreased upon Cr exposure. The elevated SAM to SAH ratio in both Cr- exposed group indicated the decreasing capacity for methylation reaction. Conclusion: Cr (III) and Cr (VI) can induce neurotoxicity by interfering with one carbon metabolism and affecting DNA methylation and histone methylation to regulate the expression of neuro-related genes. Cr exposure also influenced primary bile acid biosynthesis and phospholipid biosynthesis, which are associated with neuroprotective effects and need to be further validated.Yawen XuLi WangJun ZhuPing JiangZhan ZhangLei LiQian WuElsevierarticleChromiumNeurotoxicityMetabolismOne carbon metabolismDNA methylationHistone methylationEnvironmental pollutionTD172-193.5Environmental sciencesGE1-350ENEcotoxicology and Environmental Safety, Vol 228, Iss , Pp 112983- (2021)

Chromium induced neurotoxicity by altering metabolism in zebrafish larvae

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