TBBPA and its alternatives induce TCA cycle activation in human hepatoma cells: Molecular descriptors provide insights into metabolic effects

Disruption of cellular energy metabolism is tied to serious health conditions, with the liver playing a critical role. Tetrabromobisphenol A (TBBPA) and its alternatives, tetrachlorobisphenol A (TCBPA) and tetrabromobisphenol S (TBBPS), are flame retardants recognized for their hepatotoxicity; however, their effects on cellular energy metabolism remain inadequately elucidated. To address this, we utilized targeted metabolomics to quantify energy-related metabolites in HepG2 exposed to TBBPA and its alternatives at environmentally relevant concentrations. The exposures significantly increased α-ketoglutarate, ATP, and ADP levels, coupled with reductions in glucose 6-phosphate. The activation of the TCA cycle was substantiated by increases in nearly all associated metabolites in cells. Additionally, through the application of 3D principal component analysis and the construction of a metabolites-molecular descriptors correlation network, we recognized that Chi path descriptors, gravitational index descriptors, and moment of inertia descriptors of TBBPA and its alternatives differ from those of organic pollutants known to suppress the TCA cycle. This study underscores the disruptive impact of TBBPA and its alternatives on cellular energy metabolism, providing critical insights into their potential contributions to metabolic disorders and highlighting the utility of molecular descriptors in understanding TCA cycle activation.