Maternal-to-zygotic transition as a potential target for niclosamide during early embryogenesis

• Published in: Toxicology and applied pharmacology 2019-10, Vol.380, p.114699-114699, Article 114699
• Main Authors: Vliet, Sara M.F., Dasgupta, Subham, Sparks, Nicole R.L., Kirkwood, Jay S., Vollaro, Alyssa, Hur, Manhoi, zur Nieden, Nicole I., Volz, David C.
• Format: Article
• Language: English
• Subjects: Animals; Anthelmintics - toxicity; Cell Line; Embryo, Nonmammalian - drug effects; Embryo, Nonmammalian - metabolism; Embryonic development; Embryonic Development - drug effects; Humans; Maternal-to-zygotic transition; Metabolomics; Niclosamide; Niclosamide - toxicity; RNA - metabolism; Yolk Sac - drug effects; Yolk Sac - metabolism; Zebrafish; Zebrafish - genetics; Zebrafish - metabolism; Zygote
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2019.114699

Niclosamide is an antihelminthic drug used worldwide for the treatment of tapeworm infections. Recent drug repurposing screens have highlighted the broad bioactivity of niclosamide across diverse mechanisms of action. As a result, niclosamide is being evaluated for a range of alternative drug-repurposing 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, it is important to understand the mechanism of niclosamide toxicity during early stages of embryonic development. Previously, we showed that niclosamide induces a concentration-dependent delay in epiboly progression in the absence of effects on oxidative phosphorylation – a well-established target for niclosamide. Therefore, the overall objective of this study was to further examine the mechanism of niclosamide-induced epiboly delay during zebrafish embryogenesis. Based on this study, we found that (1) niclosamide exposure during early zebrafish embryogenesis resulted in a decrease in yolk sac integrity with a concomitant decrease in the presence of yolk sac actin networks and increase in cell size; (2) within whole embryos, niclosamide exposure did not alter non-polar metabolites and lipids, but significantly altered amino acids specific to aminoacyl-tRNA biosynthesis; (3) niclosamide significantly altered transcripts related to translation, transcription, and mRNA processing pathways; and (4) niclosamide did not significantly alter levels of rRNA and tRNA. Overall, our findings suggest that niclosamide may be causing a systemic delay in embryonic development by disrupting the translation of maternally-supplied mRNAs, an effect that may be mediated through disruption of aminoacyl-tRNA biosynthesis. •Niclosamide decreases the presence of yolk sac actin networks.•Niclosamide alters amino acids specific to aminoacyl-tRNA biosynthesis.•Niclosamide alters transcripts related to mRNA processing pathways.•Niclosamide does not significantly alter levels of rRNA and tRNA.