Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish

Quevedo, Celia; Behl, Mamta; Ryan, Kristen; Paules, Richard S.; Alday, Aintzane; Muriana, Arantza; Alzualde, Ainhoa

doi:10.1093/toxsci/kfy291

Cited by 33 publications

(23 citation statements)

References 48 publications

(57 reference statements)

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“…acenaphthenequinone, hydroquinone, and tributyltin oxide. In the developmental toxicity assay here, NOEL values for these compounds were similar to those previously reported (Knecht et al 2013;Truong et al 2014;Quevedo et al 2019;USEPA 2019). Although changes in ROS production in the zebrafish RBA were not observed here, hydroquinone has been shown to modulate ROS production in cell-based assays (Lee et al 2007).…”

Section: Compounds With Developmental But No Observable Immunotoxicitysupporting

confidence: 88%

In vivoassessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish

Phelps

Fletcher

Rodríguez-Nunez

et al. 2020

Journal of Immunotoxicology

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Currently, assessment of the potential immunotoxicity of a given agent involves a tiered approach for hazard identification and mechanistic studies, including observational studies, evaluation of immune function, and measurement of susceptibility to infectious and neoplastic diseases. These studies generally use costly low-throughput mammalian models. Zebrafish, however, offer an excellent alternative due to their rapid development, ease of maintenance, and homology to mammalian immune system function and development. Larval zebrafish also are a convenient model to study the innate immune system with no interference from the adaptive immune system. In this study, a respiratory burst assay (RBA) was utilized to measure reactive oxygen species (ROS) production after developmental xenobiotic exposure. Embryos were exposed to non-teratogenic doses of chemicals and at 96 h post-fertilization, the ability to produce ROS was measured. Using the RBA, 12 compounds with varying immune-suppressive properties were screened. Seven compounds neither suppressed nor enhanced the respiratory burst; five reproducibly suppressed global ROS production, but with varying potencies: benzo[a]pyrene, 17b-estradiol, lead acetate, methoxychlor, and phenanthrene. These five compounds have all previously been reported as immunosuppressive in mammalian innate immunity assays. To evaluate whether the suppression of ROS by these compounds was a result of decreased immune cell numbers, flow cytometry with transgenic zebrafish larvae was used to count the numbers of neutrophils and macrophages after chemical exposure. With this assay, benzo[a]pyrene was found to be the only chemical that induced a change in the number of immune cells by increasing macrophage but not neutrophil numbers. Taken together, this work demonstrates the utility of zebrafish larvae as a vertebrate model for identifying compounds that impact innate immune function at non-teratogenic levels and validates measuring ROS production and phagocyte numbers as metrics for monitoring how xenobiotic exposure alters the innate immune system.

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Section: Compounds With Developmental But No Observable Immunotoxicitysupporting

confidence: 88%

In vivoassessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish

Phelps

Fletcher

Rodríguez-Nunez

et al. 2020

Journal of Immunotoxicology

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“…It has been previously shown that changes in larval behaviour can be used as an indicator of neurotoxicity [ 7 , 8 , 25 ]. These studies tested larval behaviour following similar exposure paradigms to the aforementioned ZET assays.…”

Section: Discussionmentioning

confidence: 99%

“…The zebrafish ( Danio rerio ) is an established alternative model for toxicity testing that can provide a medium-throughput, cost-effective model that can also provide more information than can be obtained from cell line testing alone [ 1 ]. Additionally, it has been established that until zebrafish reach the protected animal stage at 5 days post fertilization (dpf) they can be considered an alternative model to animal testing [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. The zebrafish larval model of toxicity testing is now included as an Organization for Economic Cooperation and Development (OECD) Fish Embryo Toxicity (FET) model [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Zebrafish Embryo Toxicity Assay and the General and Behavioral Embryo Toxicity Assay as New Approach Methods for Chemical Screening

Achenbach

Leggiadro

Sperker

et al. 2020

Toxics

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The movement away from mammalian testing of potential toxicants and new chemical entities has primarily led to cell line testing and protein-based assays. However, these assays may not yet be sufficient to properly characterize the toxic potential of a chemical. The zebrafish embryo model is widely recognized as a potential new approach method for chemical testing that may provide a bridge between cell and protein-based assays and mammalian testing. The Zebrafish Embryo Toxicity (ZET) model is increasingly recognized as a valuable toxicity testing platform. The ZET assay focuses on the early stages of embryo development and is considered a more humane model compared to adult zebrafish testing. A complementary model has been developed that exposes larvae to toxicants at a later time point during development where body patterning has already been established. Here we compare the toxicity profiles of 20 compounds for this General and Behavioral Toxicity (GBT) assay to the ZET assay. The results show partially overlapping toxicity profiles along with unique information provided by each assay. It appears from this work that these two assays applied together can strengthen the use of zebrafish embryos/larvae as standard toxicity testing models.

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“…Wild-type zebrafish ( Danio rerio ; strain AB) were bred and housed at Biobide (San Sebastián, Spain) in accordance with standard procedures (Zebrafish Information Network) as described previously [ 3 , 51 ]. In brief, the fish were maintained in a 300-L aquarium with a maximum of 1000 fish per tank.…”

Section: Methodsmentioning

confidence: 99%

Effects of nicotinic acetylcholine receptor-activating alkaloids on anxiety-like behavior in zebrafish

Alzualde¹,

Jaka²,

Latino

et al. 2021

J Nat Med

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Alkaloids are a structurally complex group of natural products that have a diverse range of biological activities and significant therapeutic applications. In this study, we examined the acute, anxiolytic-like effects of nicotinic acetylcholine receptor (nAChR)-activating alkaloids with reported neuropharmacological effects but whose effects on anxiety are less well understood. Because α4β2 nAChRs can regulate anxiety, we first demonstrated the functional activities of alkaloids on these receptors in vitro. Their effects on anxiety-like behavior in zebrafish were then examined using the zebrafish novel tank test (NTT). The NTT is a relatively high-throughput behavioral paradigm that takes advantage of the natural tendency of fish to dive down when stressed or anxious. We report for the first time that cotinine, anatabine, and methylanatabine may suppress this anxiety-driven zebrafish behavior after a single 20-min treatment. Effective concentrations of these alkaloids were well above the concentrations naturally found in plants and the concentrations needed to induce anxiolytic-like effect by nicotine. These alkaloids showed good receptor interactions at the α4β2 nAChR agonist site as demonstrated by in vitro binding and in silico docking model, although somewhat weaker than that for nicotine. Minimal or no significant effect of other compounds may have been due to low bioavailability of these compounds in the brain, which is supported by the in silico prediction of blood–brain barrier permeability. Taken together, our findings indicate that nicotine, although not risk-free, is the most potent anxiolytic-like alkaloid tested in this study, and other natural alkaloids may regulate anxiety as well.

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Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish

Cited by 33 publications

References 48 publications

In vivoassessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish

In vivoassessment of respiratory burst inhibition by xenobiotic exposure using larval zebrafish

Comparison of the Zebrafish Embryo Toxicity Assay and the General and Behavioral Embryo Toxicity Assay as New Approach Methods for Chemical Screening

Effects of nicotinic acetylcholine receptor-activating alkaloids on anxiety-like behavior in zebrafish

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