Xenobiotics Targeting Cardiolipin Metabolism to Promote Thrombosis in Zebrafish

Abstract

Exposure to environmental pollutants is an important factor contributing to the development and severity of thrombosis. However, the important physiological molecules in the thrombotic processes affected by environmental exposures remain unknown. In this study, we show that exposure to environmental chemicals disrupts the equilibrium of cardiolipins (CLs), and directing CL synthesis promotes thrombosis. Using an untargeted metabolomics approach, approximately 3030 molecules were detected in zebrafish embryos exposed to 11 environmental chemicals and automatically clustered into a network. Interconnectivity among CLs and linoleates or isoxanthopterin was discovered through the highly consistent variations in the coregulated metabolites in the network. The chemical exposure resulted in significant upregulation of CLs through influencing the enzymatic activities of phospholipase A₂, cardiolipin synthase, and lysocardiolipin acyltransferase. Consequently, metabolic disorders of CLs affected the levels of anticardiolipin antibodies, disrupted the homeostasis between platelet thromboxane A₂ and endothelial prostacyclin, and promoted thrombotic events including heart ischemia and tachycardia. Our study thus reveals the common molecular mechanisms underlying the CL-induced thrombosis targeted by environmental exposures.