Low concentration Tetrabromobisphenol A (TBBPA) elevating overall metabolism by inducing activation of the Ras signaling pathway

Tetrabromobisphenol A (TBBPA), one of the most common flame retardants, affects neurodevelopment, disrupts the endocrine system, and increases the possibility of tumorigenesis. This study investigates the cytotoxic effects, genetic effects, and metabolic effects from exposure to low concentration TBBPA. The cell exposure was measured by mimicking the residual TBBPA concentrations in human plasma, specifically in occupational populations. Our results revealed that long-term TBBPA exposure, especially at 1 nM concentration, significantly promoted the proliferation of HepG2 cells. Furthermore, long-term TBBPA exposure can double the levels of reactive oxygen species (ROS) released from mitochondria, thereby increasing Adenosine Monophosphate activated Protein kinase (AMPK) gene expression level to promote cellular proliferation. However, ROS can also mediate the apoptosis process through the mitochondrial membrane potential (MMP). The RNA-seq analysis confirmed that the Ras signaling pathway was activated by the growth factor to mediate cell detoxification mechanism, increasing lipid and vitamin metabolic rate. Our work uncovers a cellular mechanism by which long-term exposure to low concentration TBBPA can induce the activation of the Ras signaling pathway and demonstrates potential metabolic disorder in the human hepatic cells upon plasma TBBPA exposure.