title: Warfarin, a potential pollutant in aquatic environment acting through Pxr signaling pathway and γ-glutamyl carboxylation of vitamin K-dependent proteins.
abstract: Warfarin-induced vitamin K (VK) recycling impairment is used worldwide as a rodenticide and human thromboembolic prophylactic. Since VK metabolism/signaling pathways have been conserved throughout vertebrate evolution, its release to the environment might impact on aquatic organisms. Present study assessed the toxic effect of warfarin (0, 5, 25 and 125 mg L(-1)) on zebrafish development and characterized underlying mechanisms of action through qPCR analysis of VK-related genes. Expression of pregnane X receptor (pxr), the nuclear receptor binding vitamin K, was ubiquitous in zebrafish and suggests that warfarin exposure may interfere with several biological processes. Indeed, warfarin exposure of zebrafish larvae caused hemorrhages in brain, skeletal deformities and triggered ectopic calcifications, which may be the consequence of an altered γ-carboxylation of VK-dependent proteins and/or pxr signaling. This study provides new insights into warfarin effects as a bone homeostasis disruptor and soft tissue calcification inductor, and its potential risk for aquatic environments.
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal. Electronic address: ivmonzon@ualg.pt.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Fernández
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
authors.forename: Adriana
authors.initials: A
authors.lastname: Santos
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal; Department of Biomedical Sciences and Medicine (DCBM), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
authors.forename: M Leonor
authors.initials: ML
authors.lastname: Cancela
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
authors.forename: Vincent
authors.initials: V
authors.lastname: Laizé
authors.affiliation: Centre of Marine Sciences (CCMAR), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal.
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Gavaia
mesh_terms: D000818:Animals; D000077297:Pregnane X Receptor; D011485:Protein Binding / Q000187:drug effects; D011987:Receptors, Steroid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014812:Vitamin K / Q000378:metabolism*; D014859:Warfarin / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000378:metabolism
chemical_list: D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014874:Water Pollutants, Chemical; D014812:Vitamin K; D014859:Warfarin
keywords: Pregnane X receptor; Skeletal deformities; Vitamin K; Warfarin; Zebrafish