Cardiotoxicity of tris(2-chloroethyl) phosphate exposure: Insights into the role of oxygen sensor mediated energy metabolism remodeling

Tris(2-chloroethyl) phosphate, an extensively used organophosphorus flame retardant in consumer products, has caused pervasive environmental contamination and increased human exposure, raising concerns about its cardiotoxic potential. However, the detailed toxicological profile, particularly concerning the crucial cardiac energy metabolism, and the precise mechanisms remain poorly understood. This study in C57BL/6 J mice exposed to TCEP for 36 days at varying doses revealed cardiac dysfunction, structural abnormalities, and hypoxia. Analysis of energy metabolism indicated a shift from aerobic processes (tricarboxylic acid cycle, β-oxidation, and oxidative phosphorylation) to anaerobic metabolism (glycolysis). Further restoration of energy metabolism remodeling, which was achieved by activating oxidative phosphorylation and inhibiting glycolysis, mitigated TCEP-induced cardiotoxicity, highlighting the critical role of energy metabolism remodeling in TCEP-induced cardiac injury. Mechanistically, this metabolic remodeling was primarily driven by TCEP-enhanced hyperubiquitination and degradation of prolyl hydroxylase domain 2 (PHD2), leading to the accumulation and nuclear translocation of hypoxia-inducible factor-1α (HIF-1α). This study yields key insights into the cardiotoxicity of TCEP-like OPFRs exposure, and emphasizes the role of altered cardiac energy metabolism and the oxygen-sensing pathway, thereby proposing potential intervention strategies for OPFR-induced cardiac toxicity.