Inhibition of platelet activation process upon tris (2-chloroethyl) phosphate exposure: Role of PFKP-mediated glycolysis and the pentose phosphate pathway

Tris (2-chloroethyl) phosphate (TCEP), recognized as an emerging pollutant, has been frequently detected in human blood. Maintenance of blood homeostasis is indispensable for regulating various physiological states and overall health, yet hematological toxicology of TCEP has not been extensively investigated. Platelets, a vital component of blood, are fundamental in the processes of hemostasis and thrombosis through their activation; thus, this study was designed to elucidate the effects and underlying mechanisms of TCEP on platelet activation . Utilizing an in vivo model, we conducted a proteomic analysis of platelets and found that TCEP exposure inhibited platelet activation. An ex vivo platelet evaluation system was employed to further dissect the processes of platelet activation, revealing that TCEP predominantly suppressed platelet aggregation , degranulation and clot retraction . These processes were highly dependent on energy metabolism, and TCEP was found to decrease ATP levels, primarily by impairing glycolysis and pentose phosphate pathways . Subsequent investigation into the molecular mechanisms revealed that TCEP decreased the activity of phosphofructokinase platelet (PFKP) by enhancing O-linked N-acetylglucosamine (O-GlcNAc) transferase interaction with PFKP. This study is the first to uncover the disruptive effects of TCEP on platelet activation process, providing valuable insights into the assessment of hematologic health risks associated with TCEP-like emerging pollutants exposure. • TCEP at environmental concentrations inhibits platelet activation and increases potential risk of bleeding. • TCEP decreases platelet ATP levels by interfering with glycolysis and the pentose phosphate pathway. • TCEP decreases PFKP enzyme activity via enhancing O-linked N-acetylglucosamine transferase interaction with PFKP. • A novel platform has been created for comprehensive hematologic assessment of TCEP-like emerging contaminants.