Novel Organophosphate Ester Tris(2,4-di-tert-butylphenyl)phosphate Alters Lipid Metabolism: Insights from Lipidomic Analysis and mRNA Expression

Tris(2,4-di-tert-butylphenyl)phosphate (TDTBPP), a novel organophosphate ester (OPE), has been extensively detected in various environmental and biological samples; however, its potential biological effects remain unexplored. In this study, we investigated biotransformation characteristics, alteration of lipid metabolism, and mRNA expression in primary mouse hepatocytes (PMHs) following exposure to TDTBPP. After 36-h exposure in PMHs, TDTBPP exhibited a high stability potential with no statistically significant degradation trend. Subsequently, we analyzed the disruption of lipid homeostasis in PMHs following exposure to 0-4.5 μM TDTBPP. Lipidomic analysis indicated that TDTBPP disrupted lipid homeostasis in PMHs, and several lipid classes were dysregulated, in particular, glycerolipids and glycerophospholipids. Additionally, three lipids were proposed as potential lipid biomarkers of TDTBPP exposure, including triglycerides (TGs) and phosphatidylcholines (PCs). These observations were further supported by transcriptional changes, with significant alteration observed in genes associated with lipid uptake, de novo lipogenesis, β-oxidation of fatty acids, glycerolipid metabolism, and lipid export. Overall, these findings highlight the detrimental effects of TDTBPP on lipid homeostasis, providing important insights for health risk assessments of this abundant OPE in the environment.