PUBLICATION
Niclosamide Induces Epiboly Delay During Early Zebrafish Embryogenesis
- Authors
- Vliet, S.M., Dasgupta, S., Volz, D.C.
- ID
- ZDB-PUB-180831-7
- Date
- 2018
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 166(2): 306-317 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Adenosine Triphosphate/pharmacology
- Animals
- Cell Movement/drug effects*
- Dose-Response Relationship, Drug
- Embryo, Nonmammalian
- Embryonic Development/drug effects
- Microtubules/drug effects
- Niclosamide/toxicity*
- Oxygen/metabolism
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Transcriptome/drug effects
- Tubulin/drug effects
- Tubulin Modulators
- Zebrafish/embryology*
- PubMed
- 30165700 Full text @ Toxicol. Sci.
- CTD
- 30165700
Citation
Vliet, S.M., Dasgupta, S., Volz, D.C. (2018) Niclosamide Induces Epiboly Delay During Early Zebrafish Embryogenesis. Toxicological sciences : an official journal of the Society of Toxicology. 166(2):306-317.
Abstract
Niclosamide is an antihelminthic drug used worldwide for the treatment of tapeworm infections. Recent drug repurposing screens have revealed that niclosamide exhibits diverse mechanisms of action and, as a result, demonstrates promise for a number of applications, including the treatment of cancer, bacterial infections, and Zika virus. As new applications of niclosamide will require non-oral delivery routes that may lead to exposure in utero, the objective of this study was to investigate the mechanism of niclosamide toxicity during early stages of embryonic development. Using zebrafish as a model, we found that niclosamide induced a concentration-dependent delay in epiboly progression during late-blastula and early-gastrula, an effect that was dependent on exposure during the maternal-to-zygotic transition - a period characterized by degradation of maternally-derived transcripts, zygotic genome activation, and initiation of cell motility. Moreover, we found that niclosamide did not affect embryonic oxygen consumption, suggesting that oxidative phosphorylation - a well-established target for niclosamide within intestinal parasites - may not play a role in niclosamide-induced epiboly delay. However, mRNA-sequencing revealed that niclosamide exposure during blastula and early-gastrula significantly impacted the timing of zygotic genome activation as well as the abundance of cytoskeleton- and cell cycle regulation-specific transcripts. In addition, we found that niclosamide inhibited tubulin polymerization in vitro, suggesting that niclosamide-induced delays in epiboly progression may, in part, be driven by disruption of microtubule formation and cell motility within the developing embryo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping