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

Autor: Granadeiro L; Centro de Ciências do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal., Dirks RP; ZF-screens B.V. J.H. Oortweg 19, 2333, CH Leiden, the Netherlands., Ortiz-Delgado JB; Instituto de Ciencias Marinas de Andalucía-ICMAN/CSIC, Campus Universitario Río San Pedro, Apdo. Oficial, 11510, Puerto Real, Cádiz, Spain., Gavaia PJ; Centro de Ciências do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Departamento de Ciências Biomédicas e Medicina (DCBM), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal., Sarasquete C; Instituto de Ciencias Marinas de Andalucía-ICMAN/CSIC, Campus Universitario Río San Pedro, Apdo. Oficial, 11510, Puerto Real, Cádiz, Spain., Laizé V; Centro de Ciências do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal., Cancela ML; Centro de Ciências do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Departamento de Ciências Biomédicas e Medicina (DCBM), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Algarve Biomedical Center (ABC) and Centre for Biomedical Research (CBMR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal., Fernández I; Centro de Ciências do Mar (CCMAR), Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Center for Aquaculture Research, Agrarian Technological Institute of Castile and Leon, Ctra. Arévalo, S/n. 40196 Zamarramala, Segovia, Spain. Electronic address: nacfm@hotmail.com.
Jazyk: angličtina
Zdroj: Ecotoxicology and environmental safety [Ecotoxicol Environ Saf] 2019 Oct 15; Vol. 181, pp. 559-571. Date of Electronic Publication: 2019 Jun 22.
DOI: 10.1016/j.ecoenv.2019.06.042
Abstrakt: Warfarin 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 overrepresented 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.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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