High-throughput assessment of oxidative respiration in fish embryos: Advancing adverse outcome pathways for mitochondrial dysfunction

Souders, Christopher L.; Liang, Xuefang; Wang, Xiaohong; Ector, Naomi; Zhao, Yuan H.; Martyniuk, Christopher J.

doi:10.1016/j.aquatox.2018.03.031

Cited by 57 publications

(27 citation statements)

References 90 publications

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“…A volume of 75 mL of oligomycin (75.2 mM), carbonyl cyanide-p-trifluoromethoxy phenylhydrazone (FCCP, 54 mM), and sodium azide (200 mM) was added to the injection ports to achieve final concentrations of 9.4 mM oligomycin, 6 mM FCCP, and 20 mM sodium azide in each well. The procedure of OCR measurements was conducted according to previous studies, with some modifications (Souders et al, 2018;Zhang et al, 2017). The protocol consisted of the following time cycles: 2 min for mixing, 1 min paused, and then 2 min to measure oxygen levels and pH.…”

Section: Mitochondrial Respiration Measurementmentioning

confidence: 99%

Developmental toxicity of the fungicide ziram in zebrafish (Danio rerio)

Cao

Souders

et al. 2019

Chemosphere

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Ziram is a broad spectrum pesticide that belongs to the class of dimethyl-dithiocarbamate (DTC) fungicides. The objectives of this study were to assess the effects of ziram in developing zebrafish. Ziram was highly toxic to zebrafish embryos, with a 96-h LC value of 1082.54 nM (∼0.33 mg/L). Zebrafish embryos at 6 h post-fertilization (hpf) were exposed to solvent control (0.1% DMSO), or one dose of 1, 10, 100, and 1000 nM ziram for 96 h. Ziram induced lethality in a dose-dependent manner, decreased hatching rate and heartbeat, and caused wavy deformities at 72 and 96 hpf at 100 and 1000 nM. Basal oxygen consumption rates of zebrafish at 24 hpf were decreased with 1000 nM, suggesting that ziram affects oxidative phosphorylation. We also measured the expression of transcripts associated with the oxidative stress response (sod1 and sod2) and dopamine receptor signaling at ∼96 h of exposure. There was no difference in the expression of genes related to oxidative stress, nor those related to the dopamine system. Locomotor activity was also assessed in larval zebrafish (7 dpf), and ziram increased total activity, the velocity in light zone, and total distance moved at 10 nM, while it decreased the mean time spent in the dark zone at 1 and 10 nM. Behavioral responses were dependent upon the time point and clutch examined. These data demonstrate that ziram negatively impacts embryonic development (i.e. mortality, hatching, heartbeat and notochord development) of zebrafish, decreases basal respiration of embryos, and alters behavioral responses in larvae.

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Section: Mitochondrial Respiration Measurementmentioning

confidence: 99%

Developmental toxicity of the fungicide ziram in zebrafish (Danio rerio)

Cao

Souders

et al. 2019

Chemosphere

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“…HIF1α is a sensitive oxygen responsor [[8], [9], [10], [11]] and has been widely reported to be essential for HSC formation in the AGM [7,12] and expand HSPCs [13]. However, persistent hypoxia is detrimental to embryonic development [70,71] and biological evolution [72,73], and can in some cases result in serious disease or death [74]. Thus, erythropoiesis represents a considerably more effective method for oxygen consumption.…”

Section: Discussionmentioning

confidence: 99%

The NOTCH1-dependent HIF1α/VGLL4/IRF2BP2 oxygen sensing pathway triggers erythropoiesis terminal differentiation

et al. 2020

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Hypoxia is widely considered as a limiting factor in vertebrate embryonic development, which requires adequate oxygen delivery for efficient energy metabolism, while nowadays some researches have revealed that hypoxia can induce stem cells so as to improve embryonic development. Erythroid differentiation is the oxygen delivery method employed by vertebrates at the very early step of embryo development, however, the mechanism how erythroid progenitor cell was triggered into mature erythrocyte is still not clear. In this study, after detecting the upregulation of vgll4b in response to oxygen levels, we generated vgll4b mutant zebrafish using CRISPR/Cas9, and verified the resulting impaired heme and dysfunctional erythroid terminal differentiation phenotype. Neither the vgll4b-deficient nor the γ-secretase inhibitor IX (DAPT)-adapted zebrafish were able to mediate HIF1α-induced heme generation. In addition, we showed that vgll4b mutant zebrafish were associated with an impaired erythroid phenotype, induced by the downregulation of alas2, which could be rescued by irf2bp2 depletion. Further mechanistic studies revealed that zebrafish VGLL4 sequesters IRF2BP2, thereby inhibiting its repression of alas2 expression and heme biosynthesis. These processes occur primarily via the VGLL4 TDU1 and IRF2BP2 ring finger domains. Our study also indicates that VGLL4 is a key player in the mediation of NOTCH1-dependent HIF1α-regulated erythropoiesis and can be sensitively regulated by oxygen concentrations. On the other hand, VGLL4 is a pivotal regulator of heme biosynthesis and erythroid terminal differentiation, which collectively improve oxygen metabolism.

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“…In order to investigate whether Hedgehog-mediated control of GlyT2 expression in primary neurons of rat brainstem and spinal cord is also conserved in vivo, we next used zebrafish (Danio rerio) embryos, a useful model to study CNS development, molecular mechanisms of neuropathology or behavioral neuroscience [68][69][70] . When testing the effect of a drug in the zebrafish CNS, a common practice is to use dechorionated embryos before 72 hpf when the blood-brain barrier is fully formed to ensure the compound reaches its neuronal targets [71][72][73] . GlyT2 expression in zebrafish embryos appears early at 20-24 hours post-fertilization (hpf), increases over time and is clearly detected at 36-48 hpf in dorsal interneurons 40,41,74 .…”

Section: Hedgehog Inhibition In Vivo In Zebrafish Embryos Increases Gmentioning

confidence: 99%

The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo

Rocha-Munoz

Nunez

Gomez-Lopez

et al. 2020

Preprint

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The identity of a glycinergic synapse is maintained presynaptically by the activity of a surface glycine transporter, GlyT2, which recaptures glycine back to presynaptic terminals to preserve vesicular glycine content. GlyT2 loss-of-function mutations cause Hyperekplexia, a rare neurological disease in which loss of glycinergic neurotransmission causes generalized stiffness and strong motor alterations. However, the molecular underpinnings controlling GlyT2 activity remain poorly understood. In this work, we identify the Hedgehog pathway as a robust controller of GlyT2 expression and transport activity. Modulating the activation state of the Hedgehog pathway in vitro in rodent primary spinal cord neurons or in vivo in zebrafish embryos induced a selective control in GlyT2 expression, regulating GlyT2 transport activity. Our results indicate that activation of Hedgehog reduces GlyT2 expression by decreasing its mRNA levels and increasing its ubiquitination and degradation. This work describes a new molecular link between the Hedgehog signaling pathway and presynaptic glycine availability.

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High-throughput assessment of oxidative respiration in fish embryos: Advancing adverse outcome pathways for mitochondrial dysfunction

Cited by 57 publications

References 90 publications

Developmental toxicity of the fungicide ziram in zebrafish (Danio rerio)

Developmental toxicity of the fungicide ziram in zebrafish (Danio rerio)

The NOTCH1-dependent HIF1α/VGLL4/IRF2BP2 oxygen sensing pathway triggers erythropoiesis terminal differentiation

The presynaptic glycine transporter GlyT2 is regulated by the Hedgehog pathway in vitro and in vivo

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