Developmental and metabolic toxicity of diphenyl phosphate: insights from an integrative mechanistic framework in...

Diphenyl Phosphate (DPhP), as a major metabolite and environmental pollutant of aromatic organophosphorus flame retardants, has garnered considerable attention due to its widespread occurrence in environmental matrices and potential health risks. In this study, we established an integrative framework combining network toxicology, transcriptomics, and zebrafish assays to elucidate the toxicological mechanisms of DPhP. Network toxicology and transcriptomic analyses consistently revealed that DPhP-responsive genes were predominantly enriched in pathways governing cellular energy homeostasis, including glucose-lipid metabolism and mitochondrial oxidative phosphorylation. These results collectively suggest that DPhP perturbs glucose and lipid metabolic processes, impairs mitochondrial function, and compromises ATP-generating capacity. In vivo validation using zebrafish further demonstrated pronounced metabolic reprogramming following DPhP exposure. At 25 μM, DPhP significantly elevated whole-body glucose (∼1.3-fold vs. control) and pyruvate levels (∼5-fold), and induced hepatic lipid accumulation, as evidenced by increased triglyceride (TG; ∼3-fold) and total cholesterol (T-CHO; ∼3-fold) concentrations. This metabolic shift was accompanied by a marked decline in mitochondrial membrane potential, inhibition of electron transport chain activity, and a substantial reduction in ATP content (to less than 25 % of control). These metabolic perturbations ultimately manifested as pericardial edema, impaired growth, vascular abnormalities, and concentration-dependent behavioral alterations. By delineating the cascade from mitochondrial dysfunction to systemic energy imbalance and multi-organ toxicity, this study provides novel mechanistic insights into the action of DPhP. Furthermore, the integrative paradigm linking chemical structure analysis, target prediction, omics profiling, and in vivo validation offers a versatile methodological framework for advancing mechanistic toxicology research and environmental risk assessment of emerging contaminants.