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

Granadeiro, Luís; Dirks, Ron P.; Ortiz-Delgado, Juan B.; Gavaia, Paulo J.; Sarasquete, Carmen; Laizé, Vincent; Cancela, M. Leonor; Fernández, Ignacio

doi:10.1016/j.ecoenv.2019.06.042

Cited by 15 publications

(17 citation statements)

References 98 publications

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“…Nowadays, VK is quite well known in vertebrates to be required for blood coagulation [ 35 , 36 , 37 ], skeletal and joint tissues [ 19 , 38 , 39 , 40 , 41 , 42 ], and pathological calcification and inflammation [ 37 , 43 , 44 , 45 ]. There are some reports on their potential role on redox homeostasis [ 41 , 46 , 47 ], sphingolipid [ 48 , 49 ] and glucose metabolism [ 50 ], neural development and cognitive capacities [ 20 , 48 , 51 , 52 ], as well as angiogenesis [ 53 ]. Furthermore, some evidences have been presented regarding the potential role of VK on the reproduction of mammalian [ 54 , 55 ] and fish species [ 37 , 49 , 55 ].…”

Section: Vitamin K Metabolites Sources and Metabolismmentioning

confidence: 99%

“…Thus, VK might also protect primordial and primary follicles from death if its antioxidant role in vertebrates is confirmed. In this sense, an increased oxidative stress response (at transcriptional level) in zebrafish ( Danio rerio ) embryos under VK-induced deficiency was found [ 41 ]. Nevertheless, the potential preventive antioxidant role of VK1 and VK2 is not observed for its analog, the menadione (VK3).…”

Section: The Impact Of Vitamin K In Reproductionmentioning

confidence: 99%

“…Activation of PXR markedly increases plasma concentrations of corticosterone and aldosterone, the primary glucocorticoid and mineralocorticoid in rodents, being associated to the activation of adrenal steroidogenic enzymes, including CYP11A1, CYP11B1, CYP11B2, and HSD3B2 [ 157 ]. In a vertebrate’s model for developmental biology, the zebrafish, the exposure to warfarin during embryogenesis affect the thyrotropin-releasing hormone receptor signaling pathway, at least at the transcriptomic level [ 41 ], suggesting that the VK status might influence THs synthesis and homeostasis.…”

Section: The Impact Of Vitamin K In Reproductionmentioning

confidence: 99%

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Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

2020

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Vitamin K (VK) is a fat-soluble vitamin that vertebrates have to acquire from the diet, since they are not able to de novo synthesize it. VK has been historically known to be required for the control of blood coagulation, and more recently, bone development and homeostasis. Our understanding of the VK metabolism and the VK-related molecular pathways has been also increased, and the two main VK-related pathways—the pregnane X receptor (PXR) transactivation and the co-factor role on the γ-glutamyl carboxylation of the VK dependent proteins—have been thoroughly investigated during the last decades. Although several studies evidenced how VK may have a broader VK biological function than previously thought, including the reproduction, little is known about the specific molecular pathways. In vertebrates, sex differentiation and gametogenesis are tightly regulated processes through a highly complex molecular, cellular and tissue crosstalk. Here, VK metabolism and related pathways, as well as how gametogenesis might be impacted by VK nutritional status, will be reviewed. Critical knowledge gaps and future perspectives on how the different VK-related pathways come into play on vertebrate’s reproduction will be identified and proposed. The present review will pave the research progress to warrant a successful reproductive status through VK nutritional interventions as well as towards the establishment of reliable biomarkers for determining proper nutritional VK status in vertebrates.

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Section: Vitamin K Metabolites Sources and Metabolismmentioning

confidence: 99%

Section: The Impact Of Vitamin K In Reproductionmentioning

confidence: 99%

Section: The Impact Of Vitamin K In Reproductionmentioning

confidence: 99%

See 1 more Smart Citation

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

2020

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“…Nowadays, VK is known to be required for blood coagulation [49,50], skeletal tissue [21] and redox [23,51] homeostasis, sphingolipid [52] and glucose metabolism [53], neural development and cognitive capacities [52,[54][55][56], pathological calcification and inflammation [57][58][59], angiogenesis [60], and reproduction [61][62][63]. Studies in fish also suggest that VK is required for blood coagulation [16,64], skeletal development and skeletal tissues homeostasis [15,17,18], redox homeostasis [18], sphingolipid metabolism [14], brain development and cognitive capacities [19], pathological calcification and inflammation [16], and reproduction [14,16,65], reinforcing the idea of a well conserved function of VK throughout vertebrate evolution [26,66]. Nevertheless, the identification and characterization of the different molecular pathways where VK acts in vertebrates development and physiology, particularly how they respond to relevant physiological conditions, still needs to be determined in order to identify potential suitable biomarkers of VK nutritional status [67][68][69].…”

Section: Discussionmentioning

confidence: 99%

“…In general, VK nutritional requirements were considered to be low, as VK was thought to be mainly involved in blood coagulation, and no major signs of bleeding disorders were observed in fish with low VK dietary levels [12]. In fish species, the key role of VK in biological processes, such as sex hormone synthesis/release and reproductive performance [14], skeletal development and maintenance [15][16][17][18], neural development and cognitive capacities [19], and redox system homeostasis, vasculogenesis and visual phototransduction [18], has been evidenced, and higher VK nutritional requirements during early developmental stages than previously thought were suggested [15,16,18].…”

Section: Introductionmentioning

confidence: 99%

New Insights on Vitamin K Metabolism in Senegalese sole (Solea senegalensis) Based on Ontogenetic and Tissue-Specific Vitamin K Epoxide Reductase Molecular Data

Beato

Marques

Laizé

et al. 2020

IJMS

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Vitamin K (VK) is a key nutrient for several biological processes (e.g., blood clotting and bone metabolism). To fulfill VK nutritional requirements, VK action as an activator of pregnane X receptor (Pxr) signaling pathway, and as a co-factor of γ-glutamyl carboxylase enzyme, should be considered. In this regard, VK recycling through vitamin K epoxide reductases (Vkors) is essential and should be better understood. Here, the expression patterns of vitamin K epoxide reductase complex subunit 1 (vkorc1) and vkorc1 like 1 (vkorc1l1) were determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1 and ssvkorc1l1 were determined and peptide sequences were found to be evolutionarily conserved. During larval development, expression of ssvkorc1 showed a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreased until 24 h post-fertilization, and remained constant afterwards. Both ssvkors were ubiquitously expressed in adult tissues, and highest expression was found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 was differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency. The present work provides new and basic molecular clues evidencing how VK metabolism in marine fish is sensitive to nutritional and environmental conditions.

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In Silico Analysis to Identify Molecular Targets for Chemicals of Concern: The Case Study of Flocoumafen, an Anticoagulant Pesticide

Coronado-Posada

Mercado-Camargo

Olívero-Verbel

2021

Enviro Toxic and Chemistry

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Rodenticides are pesticides used worldwide, with little information available regarding health consequences in wildlife and humans. The aim of the present study was to use virtual screening to identify potential targets for flocoumafen, a superwarfarin rodenticide. Blind docking of more than 841 human proteins was carried out employing AutoDock Vina. The strength of the ligand interaction with the proteins was quantified based on the binding affinity score (kcal/mol). Results indicate that flocoumafen could be a promiscuous ligand for diversity of cellular protein targets. The best complexes were obtained for prostaglandin F synthase (−14.2 kcal/mol) and serum albumin (−14.0 kcal/mol) followed by glucocorticoid receptor 2, matrix metalloproteinase-9, nuclear receptor ROR-alpha, and activin receptor type-1, all with values equal or better than −13.5 kcal/mol. Docking method validation based on the root-mean-square deviation showed that flocoumafen had good capability to predict corresponding co-crystallized poses; and molecular dynamics simulations suggested the complex with greater binding affinity was thermodynamically stable. Protein-protein interaction networks built with main protein targets revealed that protein kinase B (AKT1), ribosomal protein S6 kinase B1 (RPS6KB1), phosphatidylinositol-4,5bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), retinoid X receptor alpha (RXRA), and protein phosphatase 2 catalytic subunit alpha (PPP2CA) were major hub proteins, whereas the gene ontology analysis reported that cellular response to endogenous stimulus, protein binding, and the TOR complex were the biological processes, molecular function, and cell component enrichments, respectively. These results should motivate more ecotoxicity testing for flocoumafen and other superwarfarins, as well as precautionary legislation to minimize exposure to these highly toxic chemicals.

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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

Cited by 15 publications

References 98 publications

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

Vitamin K in Vertebrates’ Reproduction: Further Puzzling Pieces of Evidence from Teleost Fish Species

New Insights on Vitamin K Metabolism in Senegalese sole (Solea senegalensis) Based on Ontogenetic and Tissue-Specific Vitamin K Epoxide Reductase Molecular Data

In Silico Analysis to Identify Molecular Targets for Chemicals of Concern: The Case Study of Flocoumafen, an Anticoagulant Pesticide

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