Bis (2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) is an extensively used novel brominated flame retardant that is present ubiquitously in the environment and in biota. However, there is inadequate data on its potential hepatotoxicity to humans. In this study, high-coverage quantitative metabolomics based on 12C-/13C-dansylation labeling LC-MS was performed for the first time to assess the metabolic perturbations and underlying mechanisms of TBPH on human hepatocytes. HepG2 cells were exposed to TBPH at dosages of 0.1,1,10 μM for 24 or 72 h. Overall, 1887 and 1364 amine/phenol-containing metabolites were relatively quantified in cells and culture supernatant. Our results revealed that exposure to 0.1 μM TBPH showed little adverse effects, whereas exposure to 10 μM TBPH for 24 h enhanced intracellular protein catabolism and disrupted energy and lipid homeostasis-related pathways such as histidine metabolism, pantothenate and CoA biosynthesis, alanine, aspartate and glutamate metabolism. Nevertheless, most of these perturbations returned to the same levels as controls after 72 h of exposure. Additionally, prolonged TBPH exposure increased oxidative stress, as reflected by marked disturbances in taurine metabolism. This study sensitively revealed the dysregulations of intracellular and extracellular metabolome induced by TBPH, providing a comprehensive understanding of metabolic responses of cells to novel brominated flame retardants.
Keywords: Bis (2-ethylhexyl)-2,3,4,5-tetrabromophthalate; Chemical isotope labeling; Hepatotoxicity; LC-MS; Metabolomics.
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