Zebrafish models for assessing developmental and reproductive toxicity

He, Jiaxun; Gao, Jimin; Huang, Changjiang; Li, Chunqi

doi:10.1016/j.ntt.2014.01.006

Cited by 186 publications

(93 citation statements)

References 98 publications

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“…The temporary delay in hatching could also be associated with the decrease in body lengths seen in triadimefon treated embryos. Toxic effects on somitic development, skeletal and/or muscle development, all phenotypes discussed below in this paper, might be the causative reason behind the shortening of body length [21]. …”

Section: Resultsmentioning

confidence: 99%

Zebrafish as an Alternative Vertebrate Model for Investigating Developmental Toxicity—The Triadimefon Example

Zoupa

Machera

2017

IJMS

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Triadimefon is a widely used triazole fungicide known to cause severe developmental defects in several model organisms and in humans. The present study evaluated in detail the developmental effects seen in zebrafish embryos exposed to triadimefon, confirmed and expanded upon previous phenotypic findings and compared them to those observed in other traditional animal models. In order to do this, we exposed embryos to 2 and 4 µg/mL triadimefon and evaluated growth until 120 h post-fertilization (hpf) through gross morphology examination. Our analysis revealed significant developmental defects at the highest tested concentration including somite deformities, severe craniofacial defects, a cleft phenotype along the three primary neural divisions, a rigorously hypoplastic or even absent mandible and a hypoplastic morphology of the pharyngeal arches. Interestingly, massive pericardial edemas, abnormal shaped hearts, brachycardia and inhibited or absent blood circulation were also observed. Our results revealed that the presented zebrafish phenotypes are comparable to those seen in other organism models and those derived from human observations as a result of triadimefon exposure. We therefore demonstrated that zebrafish provide an excellent system for study of compounds with toxic significance and can be used as an alternative model for developmental toxicity studies to predict effects in mammals.

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Section: Resultsmentioning

confidence: 99%

Zebrafish as an Alternative Vertebrate Model for Investigating Developmental Toxicity—The Triadimefon Example

Zoupa

Machera

2017

IJMS

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“…Zebrafish is emerging as a predictive animal model for in vivo assessment of drug efficacy, toxicity, and safety. 23,[29][30][31][32] We use zebrafish because of their many advantages such as short generation times, amenability for large-scale screening, high fecundity, ease of in vitro fertilization, and transparency. 4,33,34 Other important advantages of the zebrafish as an animal model are that the morphological and molecular basis of tissues and organs is either identical or similar to other vertebrates, including humans.…”

Section: Discussionmentioning

confidence: 99%

A Zebrafish Thrombosis Model for Assessing Antithrombotic Drugs

Zhu

Liu²,

Guo³

et al. 2016

Zebrafish

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Thrombosis is a leading cause of death and the development of effective and safe therapeutic agents for thrombotic diseases has been proven challenging. In this study, taking advantage of the transparency of larval zebrafish, we developed a larval zebrafish thrombosis model for drug screening and efficacy assessment. Zebrafish at 2 dpf (days post fertilization) were treated with phenylhydrazine (PHZ) and a testing drug for 24 h. Tested drugs were administered into the zebrafish either by direct soaking or circulation microinjection. Antithrombotic efficacy was quantitatively evaluated based on our previously patented technology characterized as an image analysis of the heart red blood cells stained with O-dianisidine staining. Zebrafish at 2 dpf treated with PHZ at a concentration of 1.5 μM for a time period of 24 h were determined as the optimum conditions for the zebrafish thrombosis model development. Induced thrombosis in zebrafish was visually confirmed under a dissecting stereomicroscope and quantified by the image assay. All 6 human antithrombotic drugs (aspirin, clopidogrel, diltiazem hydrochloride injection, xuanshuantong injection, salvianolate injection, and astragalus injection) showed significant preventive and therapeutic effects on zebrafish thrombosis (p < 0.05, p < 0.01, & p < 0.001) in this zebrafish thrombosis model. The larval zebrafish thrombosis model developed and validated in this study could be used for in vivo thrombosis studies and for rapid screening and efficacy assessment of antithrombotic drugs.

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“…72 hours later, eight embryos were transferred to a 96-well plate where they were dissolved for absorbance reading at 340nm. At this stage, this process also allowed us to determine drug toxicity, since drugs would only be included in the analysis if 80% or more of embryos survived the treatment, and the embryos did not show any behavioural or morphological defects of developmental toxicity as previously described [10]. Toxic drugs were rescreened at half the starting concentration (an average of 1 μM).…”

Section: Resultsmentioning

confidence: 99%

Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics

et al. 2016

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Phenotype-guided re-profiling of approved drug molecules presents an accelerated route to developing anticancer therapeutics by bypassing the target-identification bottleneck of target-based approaches and by sampling drugs already in the clinic. Further, combinations incorporating targeted therapies can be screened for both efficacy and toxicity. Previously we have developed an oncogenic-RAS-driven zebrafish melanoma model that we now describe display melanocyte hyperplasia while still embryos. Having devised a rapid method for quantifying melanocyte burden, we show that this phenotype can be chemically suppressed by incubating V12RAS transgenic embryos with potent and selective small molecule inhibitors of either MEK or PI3K/mTOR. Moreover, we demonstrate that combining MEK inhibitors (MEKi) with dual PI3K/mTOR inhibitors (PI3K/mTORi) resulted in a super-additive suppression of melanocyte hyperplasia. The robustness and simplicity of our novel screening assay inspired us to perform a modest screen of FDA approved compounds for their ability to potentiate MEKi PD184352 or PI3K/mTORi NVPBEZ235 suppression of V12RAS-driven melanocyte hyperplasia. Through this route, we confirmed Rapamycin as a compound that could synergize with MEKi and even more so with PI3K/mTORi to suppress melanoma development, including suppressing the growth of cultured human melanoma cells. Further, we discovered two additional compounds—Disulfiram and Tanshinone—that also co-operate with MEKi to suppress the growth of transformed zebrafish melanocytes and showed activity toward cultured human melanoma cells. In conclusion, we provide proof-of-concept that our phenotype-guided screen could be used to identify compounds that affect melanoma development and prompt further evaluation of Disulfiram and Tanshinone as possible partners for combination therapy.

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Zebrafish models for assessing developmental and reproductive toxicity

Cited by 186 publications

References 98 publications

Zebrafish as an Alternative Vertebrate Model for Investigating Developmental Toxicity—The Triadimefon Example

Zebrafish as an Alternative Vertebrate Model for Investigating Developmental Toxicity—The Triadimefon Example

A Zebrafish Thrombosis Model for Assessing Antithrombotic Drugs

Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics

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