Copper inhibits hatching of fish embryos via inducing reactive oxygen species and down-regulating Wnt signaling

Zhang, Yanjun; Zhang, Ruitao; Sun, Haojie; Chen, Qi; Yu, Xiao; Zhang, Ting; Yi, Ming; Liu, Jing‐Xia

doi:10.1016/j.aquatox.2018.10.015

Cited by 42 publications

(21 citation statements)

References 47 publications

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“…The transfer of copper to mitochondria was assumed to be blocked in copper stressed cox17 -/mutant, and cox17 -/embryos fail to produce ROS after copper stimulation (47), but defects of CNS myelin and axon were still observed in this study, suggesting that copper-induced myelin and axon defects might not . CC-BY 4.0 International license perpetuity.…”

Section: Discussionmentioning

confidence: 60%

Copper stress induces zebrafish central neural system myelin defects via WNT/NOTCH-hoxb5b signaling and pou3f1/fam168a/fam168b DNA methylation

Zhang

Guan

Liu

et al. 2020

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Unbalanced copper (Cu 2+ ) homeostasis is associated with neurological development defects and diseases. However, the molecular mechanisms remain elusive. Here, central neural system (CNS) myelin defects and down-regulated expression of Wnt/Notch signaling and their down-stream mediator hoxb5b were observed in Cu 2+ stressed zebrafish larvae. Loss/knockdown-of-function of hoxb5b phenocopied the myelin and axon defects observed in Cu 2+ stressed embryos. Meanwhile, activation of Wnt/Notch signaling and ectopic expression of hoxb5b could rescue copper-induced myelin defects, suggesting Wnt&Notch-hoxb5b axis mediated Cu 2+ induced myelin and axon defects. Additionally, whole genome DNA methylation sequencing unveiled that a novel gene fam168b, similar to pou3f1/2, exhibited significant promoter hypermethylation and reduced expression in Cu 2+ stressed embryos. The hypermethylated locus in fam168b promoter acted pivotally in its transcription, and loss/knockdown of fam168b/pou3f1 also induced myelin defects. Moreover, this study unveiled that fam168b/pou3f1 and hoxb5b axis acted in a seesaw manner during fish embryogenesis, and demonstrated that copper induced the down-regulated expression of the Wnt&Notch-hoxb5b axis dependent of the function of copper transporter cox17, coupled with the promoter methylation of genes fam168b/pou3f1 and their subsequent down-regulated expression dependent of the function of another transporter atp7b, making joint contributions to myelin defects in embryos. Those data will shed some light on the linkage of unbalanced copper homeostasis with specific gene promoter methylation and signaling transduction as well as the resultant neurological development defects and diseases.

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Section: Discussionmentioning

confidence: 60%

Copper stress induces zebrafish central neural system myelin defects via WNT/NOTCH-hoxb5b signaling and pou3f1/fam168a/fam168b DNA methylation

Zhang

Guan

Liu

et al. 2020

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…In the presence of ENMs, inhibition of the protease activity needed for hatch (assumed zebrafish hatching enzyme, Zhe1) has been demonstrated (Ong et al, 2014b). How Boyle et al Ecotoxicology and Environmental Safety xxx (xxxx) xxx-xxx ever, oxidative stress from CuO ENM exposure may preferentially reduce locomotor activity of the embryo so that the animal cannot break through the chorion, rather than altering the gene expression controlling the secretion of the protease (Zhang et al, 2018). The precise mechanism by which oxidative stress from CuO ENMs reduces motility in the embryo is less clear, but for example, could involve damage to the skeletal muscle fibres on the flank of this fish (observed in trout, Al-Bairuty et al, 2013) or respiratory distress (i.e., inability to exercise).…”

Section: Toxicity Of Cuso 4 and Cuo Enms At Low Phmentioning

confidence: 99%

Toxicities of copper oxide nanomaterial and copper sulphate in early life stage zebrafish: Effects of pH and intermittent pulse exposure

Boyle

Clark

Handy

2020

Ecotoxicology and Environmental Safety

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Effort has been made to standardise regulatory ecotoxicity tests for engineered nanomaterials (ENMs), but the environmental realism of altered water quality and/or pulse exposure to these pollutants should be considered. This study aimed to investigate the relative toxicity to early life-stage zebrafish of CuO ENMs at acid pH and then under pulse exposure conditions, all compared to CuSO 4 . At all pH values, CuSO 4 was more toxic to zebrafish than CuO ENMs. Additions of H + were protective of CuSO 4 toxicity, with median lethal concentrations LC 50 (with 95% confidence intervals) of: 0.36 (0.33-0.40), 0.22 (0.20-0.24) and 0.27 (0.25-0.29) mg L −1 at pH 5, pH 6 and pH 7, respectively. In contrast, the toxicity of CuO ENMs increased with acidity; LC 50 values were: 6.6 (4.5-8.5), 19.4 (11.6-27.2) and >100 mg L −1 at pH 5, pH 6 and pH 7, respectively. The increased toxicity of the CuO ENMs in acid water corresponded with greater dissolution of dissolved Cu from the particles at low pH, suggesting free Cu 2+ ion delivery to the zebrafish was responsible for the pH-effect. In continuous 96 h exposures to the substances at the LC 10 values and at pH 6, both CuSO 4 and CuO ENMs caused Cu accumulation, inhibition of Na + /K + -ATPase and depletions in total glutathione in zebrafish. However, two 24 h pulses of CuSO 4 or CuO ENMs at the same peak concentration caused similar effects to the continuous 96 h exposure, despite the shorter exposure durations of the former; suggesting that the pulses were more hazardous than the continuous exposure. In conclusion, the current water quality correction for pH with respect to Cu toxicity to freshwater fish should not be applied to the nano form. Crucially, CuO ENMs are more toxic in pulse than continuous exposure and new corrections for both water pH and the Cu exposure profile are needed for environmental risk assessment.

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“…The transfer of copper to mitochondria was assumed to be blocked in copper stressed cox17 -/- mutant, and cox17 -/- embryos fail to produce ROS after copper stimulation (47), but defects of CNS myelin and axon were still observed in this study, suggesting that copper-induced myelin and axon defects might not be essentially mediated by copper-induced ROS and by the function of cox17 alone. Moreover, in this study, endoplasmic reticulum (ER) stress alleviant PBA was found unable to recover the expression of mbp in Cu 2+ stressed WT embryos, suggesting copper-induced ER stresses might not alone mediate copper-induced CNS myelin development defects.…”

Section: Discussionmentioning

confidence: 68%

Copper Induces Zebrafish Central Neural System Myelin Defects: the Regulatory Mechanisms in Wnt/Notch-hoxb5bSignaling and Underlying DNA Methylation

Guan

Zhao

et al. 2019

Preprint

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29 Unbalanced copper (Cu 2+ ) homeostasis is associated with neurological development defects and 30 diseases. However, the molecular mechanisms remain elusive. Here, central neural system (CNS) myelin 31 defects and down-regulated expression of Wnt/Notch signaling and their down-stream mediator hoxb5b 32 were observed in Cu 2+ stressed zebrafish larvae. Loss/knockdown-of-function of hoxb5b phenocopied 33 the myelin and axon defects observed in Cu 2+ stressed embryos. Meanwhile, activation of Wnt/Notch 34 signaling and ectopic expression of hoxb5b could rescue copper-induced myelin defects, suggesting 35 Wnt&Notch-hoxb5b axis mediated Cu 2+ induced myelin and axon defects. Additionally, whole genome 36 DNA methylation sequencing unveiled that a novel gene fam168b, similar to pou3f1/2, exhibited 37 significant promoter hypermethylation and reduced expression in Cu 2+ stressed embryos. The 38 hypermethylated locus in fam168b promoter acted pivotally in its transcription, and loss/knockdown of 39 fam168b/pou3f1 also induced myelin defects. Moreover, this study unveiled that fam168b/pou3f1 and 40 hoxb5b axis acted in a seesaw manner during fish embryogenesis, and demonstrated that copper induced 41 the down-regulated expression of the Wnt&Notch-hoxb5b axis dependent of the function of copper 42 transporter cox17, coupled with the promoter methylation of genes fam168b/pou3f1 and their subsequent 43 down-regulated expression dependent of the function of another transporter atp7b, making joint 44 contributions to myelin defects in embryos. Those data will shed some light on the linkage of unbalanced 45 copper homeostasis with specific gene promoter methylation and signaling transduction as well as the 46 resultant neurological development defects and diseases.47 48 Author summary 49In this study, we first unveiled that copper induced central neural system (CNS) myelin defects via 50 3 down-regulating Wnt/Notch-hoxb5b signaling, and parallel with hypermethylating promoters of genes 51 fam168b/pou3f2 and their subsequent down-regulated expression. Additionally, we unveiled that 52 fam168b/pou3f1 and hoxb5b axis acted in a seesaw manner during fish embryogenesis. Genetically, we 53 unveiled that copper was trafficked to mitochondrion via cox17 then led to the down-regulation of 54 Wnt&Notch-hoxb5b axis, and was trafficked to trans-Golgi network via atp7b to induce the 55 hypermethylation and the down-regulated expression of pou3f1/fam168b genes, making joint 56 contributions to myelin defects in embryos.

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Copper inhibits hatching of fish embryos via inducing reactive oxygen species and down-regulating Wnt signaling

Cited by 42 publications

References 47 publications

Copper stress induces zebrafish central neural system myelin defects via WNT/NOTCH-hoxb5b signaling and pou3f1/fam168a/fam168b DNA methylation

Copper stress induces zebrafish central neural system myelin defects via WNT/NOTCH-hoxb5b signaling and pou3f1/fam168a/fam168b DNA methylation

Toxicities of copper oxide nanomaterial and copper sulphate in early life stage zebrafish: Effects of pH and intermittent pulse exposure

Copper Induces Zebrafish Central Neural System Myelin Defects: the Regulatory Mechanisms in Wnt/Notch-hoxb5bSignaling and Underlying DNA Methylation

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