Warfarin, a potential pollutant in aquatic environment acting through Pxr signaling pathway and γ-glutamyl carboxylation of vitamin K-dependent proteins

10 páginas, 7 figuras, 1 tabla.

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.

The authors are gratefully to Patrícia Diogo for technical assistance during sampling procedures. IF acknowledges the financial support of the Portuguese Fundation for Science and Technology (FCT) through the post-doctoral grant SFRH/BDP/82049/2011. This work was partly funded by the FCT through SPECIAL K (PDTC/MAR/ 105152/2008) and AQUATOX (PTDC/MAR/112992/2009) projects and by the European Commission (ERDF-COMPETE) through PEstC/MAR/LA0015/2011 project.

Peer reviewed