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Warfarin-exposed zebrafish embryos resembles human warfarin embryopathy in a dose and developmental-time dependent manner - From molecular mechanisms to environmental concerns

2019-10Journal article Restricted access
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dc.contributor.authorGranadeiro, Luis
dc.contributor.authorDirks, Ron P.
dc.contributor.authorOrtiz-Delgado, Juan B.
dc.contributor.authorJ. Gavaia, Paulo
dc.contributor.authorSarasquete, Carmen
dc.contributor.authorLaizé, Vincent
dc.contributor.authorLeonor Cancela, M.
dc.contributor.authorI, Fernández
dc.date.accessioned2020-07-24T10:51:19Z
dc.date.available2020-10-01T00:30:11Z
dc.date.issued2019-10
dc.description.abstractWarfarin is the most worldwide used anticoagulant drug and rodenticide. Since it crosses placental barrier it can induce warfarin embryopathy (WE), a fetal mortality in neonates characterized by skeletal deformities in addition to brain hemorrhages. Although the effects of warfarin exposure in aquatic off target species were already described, the particular molecular toxicological mechanisms during early development are still unclear. Here, we used zebrafish (Danio rerio) to describe and compare the developmental effects of warfarin exposure (0, 15.13, 75.68 and 378.43 mM) on two distinct early developmental phases (embryos and eleuthero-embryos). Although exposure to both developmental phases induced fish mortality, only embryos exposed to the highest warfarin level exhibited features mimicking mammalian WE, e.g. high mortality, higher incidence of hemorrhages and altered skeletal development, among other effects. To gain insights into the toxic mechanisms underlying warfarin exposure, the transcriptome of embryos exposed to warfarin was explored through RNA-Seq and compared to that of control embryos. 766 differentially expressed (564 up- and 202 down-regulated) genes were identified. Gene Ontology analysis revealed particular cellular components (cytoplasm, extracellular matrix, lysosome and vacuole), biological processes (mainly amino acid and lipid metabolism and response to stimulus) and pathways (oxidative stress response and apoptosis signaling pathways) being significantly over-represented in zebrafish embryos upon warfarin exposure. Protein-protein interaction further evidenced an altered redox system, blood coagulation and vasculogenesis, visual phototransduction and collagen formation upon warfarin exposure. The present study not only describes for the first time the WE in zebrafish, it provides new insights for a better risk assessment, and highlights the need for programming the rat eradication actions outside the fish spawning season to avoid an impact on off target fish community. The urge for the development of more species-specific anticoagulants for rodent pest control is also highlighted.
dc.description.sponsorshipPortuguese Foundation for Science and TechnologyPortuguese Foundation for Science and Technology [UID/Multi/04326/2019]
dc.description.sponsorshipproject MET2VI - Ministerio de Ciencia, Innovacion y Universidades of the Spanish Government [RTI2018-099029-A-I00]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1016/j.ecoenv.2019.06.042
dc.identifier.issn0147-6513
dc.identifier.issn1090-2414
dc.identifier.urihttp://hdl.handle.net/10400.1/14217
dc.language.isoeng
dc.peerreviewedyes
dc.publisherAcademic Press
dc.relationAQUATOX - Assessment of mineralogenic toxicity of aquatic pollutants
dc.subjectPregnane X receptor
dc.subjectExpression in-vivo
dc.subjectVitamin-K epoxide
dc.subjectAnticoagulant rodenticides
dc.subjectTargeted disruption
dc.subjectAquatic environment
dc.subjectSignaling pathway
dc.subjectGene
dc.subjectBrodifacoum
dc.subjectDeficiency
dc.titleWarfarin-exposed zebrafish embryos resembles human warfarin embryopathy in a dose and developmental-time dependent manner - From molecular mechanisms to environmental concerns
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleAQUATOX - Assessment of mineralogenic toxicity of aquatic pollutants
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMAR%2F112992%2F2009/PT
oaire.citation.endPage571
oaire.citation.startPage559
oaire.citation.titleEcotoxicology and Environmental Safety
oaire.citation.volume181
oaire.fundingStream3599-PPCDT
person.familyNameGranadeiro
person.familyNameGavaia
person.familyNameLaizé
person.familyNameCancela
person.familyNameFernández Monzón
person.givenNameLuis
person.givenNamePaulo
person.givenNameVincent
person.givenNameM. Leonor
person.givenNameIgnacio Valentín
person.identifier117775
person.identifier.ciencia-id3212-D91A-8A9A
person.identifier.ciencia-idB619-FC16-D007
person.identifier.ciencia-id111D-018F-70FE
person.identifier.orcid0000-0002-9582-1957
person.identifier.orcid0000-0001-9565-9198
person.identifier.orcid0000-0003-3114-6662
person.identifier.orcid0000-0002-8088-7902
person.identifier.ridA-6470-2011
person.identifier.ridB-4463-2008
person.identifier.ridB-1527-2017
person.identifier.scopus-author-id6507104377
person.identifier.scopus-author-id6602982778
person.identifier.scopus-author-id24484817300
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticle
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