Ethylhexyl Diphenyl Phosphate Mediates Oxidative Stress and Energy Metabolism Abnormalities by Affecting Glycolipid Metabolism in Zebrafish during Early Development: Key Regulatory Role of the Peroxisome Proliferator-Activated Receptor Signaling Pathway

2-Ethylhexyl diphenyl phosphate (EHDPP), a widely used alternative flame retardant, raised increasing concern due to its potential developmental and metabolic toxicity. This study evaluated the toxicity of EHDPP on early zebrafish development within a concentration range of 5–500 μg/L, with a particular emphasis on metabolic disturbances and their underlying mechanisms. Exposure to EHDPP induced developmental abnormalities and disturbances in glucose and lipid homeostasis, accompanied by mitochondrial dysfunction, excessive reactive oxygen species generation, and ATP depletion. Transcriptomic analysis identified significant enrichment of pathways associated with glucose and lipid metabolism, mitochondrial function, and peroxisome proliferator-activated receptor (PPAR) signaling. Integrated mRNA, protein, and dual-luciferase reporter analyses demonstrated that EHDPP at 50 and 500 μg/L altered PPAR transcriptional activity, with suppression of PPARα and activation of PPARγ. Pharmacological and genetic interventions further revealed distinct subtype-specific roles of PPAR signaling in regulating lipid accumulation, glucose metabolism, mitochondrial function, and oxidative stress. A deleterious feedback loop, in which oxidative stress and mitochondrial dysfunction further exacerbated metabolic disturbances, culminated in ATP depletion and energy deficiency, ultimately contributing to developmental toxicity. These findings demonstrated that EHDPP disrupted metabolic homeostasis through interference with PPAR signaling, providing novel insights into its toxicological mechanisms and potential environmental health risks.