PPARα-dependent lipid metabolic disruption mediates triphenyl phosphate–induced hepato- and neurotoxicity in zebrafish

The extensive use of triphenyl phosphate (TPhP) has resulted in its ubiquity in aquatic ecosystems, raising significant concerns about its escalating risks to aquatic organisms. In this study, we employed adult and larval zebrafish (Danio rerio) as model organisms to assess the adverse effects of TPhP exposure on aquatic life. The objectives were to evaluate TPhP-induced hepatotoxicity and neurotoxicity and the role of lipid metabolism in mediating these toxic effects. The results demonstrated that TPhP exposure led to alterations in body weight, length, and body mass index (BMI), along with changes in brain and liver somatic indices in zebrafish. Through comprehensive analyses of histopathological changes, transcriptional profiles, biochemical markers, and neurobehavioral assays, TPhP was shown to induce both morphological and functional impairments in the brain and liver. In TPhP-exposed larvae, reduced tissue integrity and altered spatial distribution of brain and hepatic tissues were observed. Notably, changes in the expression of neurodevelopmental and lipid metabolism-related genes in larvae mirrored those detected in adult zebrafish, indicating conserved toxic mechanisms across life stages. Mechanistically, TPhP exposure induced oxidative stress in both brain and liver tissues and suppressed the expression of PPARα, as well as its downstream genes involved in fatty acid β-oxidation and lipid homeostasis. Consequently, hepatic triglyceride (TG) and total cholesterol (T-CHO) levels were significantly decreased, whereas free fatty acid (FFA) content was elevated. Thus, TPhP inhibits PPARα signaling via oxidative stress, leading to lipid metabolic dysfunction and subsequent damage to neural and hepatic tissues. This study provides robust evidence of TPhP-induced hepatotoxicity and neurotoxicity in zebrafish, and elucidates the critical role of PPARα-mediated disruption of lipid metabolism in these toxic pathways, thereby enhancing our understanding of the ecological risks posed by organophosphate flame retardants.