EHDPP has the potential to impair mitochondrial fatty acid oxidation through inhibition of Cpt1A expression in mice

2-Ethylhexyl diphenyl phosphate (EHDPP), an aromatic organophosphate flame retardant (OPFR), is widely used in electronics, plastics, and textiles. While previous research has primarily focused on in vitro assays, the hepatotoxicity of EHDPP in mammals remains unclear. In the present study, six-week-old C57BL/6 mice are administered EHDPP via oral gavage for 28 days. First, EHDPP exposure leads to decreased body weights and significant hepatic accumulation of EHDPP (23.1 ng/g). Hepatic H&E staining, coupled with significantly elevated serum AST and ALT levels, demonstrates that the accumulation of EHDPP induces liver injury and inflammation. Targeted metabolomic analysis indicates reduced levels of free carnitine and acyl-carnitines in blood. RT-qPCR results confirm the marked suppression of key genes involved in hepatic lipid metabolism. Transmission electron microscopy (TEM) further reveals mitochondrial ultrastructural alterations following EHDPP exposure. Hepatic transcriptomic analysis identifies 79 and 579 differentially expressed genes (DEGs) in the EH-L and EH-H groups, respectively. Notably, Cyp2b10 displays a markedly high fold change in both the EH-L and EH-H groups. Furthermore, KEGG pathway enrichment and protein-protein interaction (PPI) analyses both exhibit that EHDPP exposure mainly affects lipid metabolism and drug metabolism. Within the PPI network modules, Cpt1a is identified as a critical hub protein. Molecular docking analysis predicts a potential interaction between EHDPP and the Cpt1A protein, and hepatic Cpt1A protein levels are significantly decreased after EHDPP exposure. Collectively, these findings provide novel insights into the mammalian health risks associated with EHDPP exposure.