Cytotoxicity of TBBPA and effects on proliferation, cell cycle and MAPK pathways in mammalian cells

Poly-brominated flame retardants are ecotoxicologically relevant chemicals that can show high persistency in environmental samples and bioaccumulation in marine and fresh water animals. One of the most widely used compound is tetrabromobisphenol A (TBBPA). Until today, the toxicological data are rather fragmentary. Our studies on acute and sub-acute toxic effects with established cell lines demonstrate that TBBPA interferes with cellular signaling pathways. Cell viability is significantly reduced in a time- and concentration-dependent manner. The observed EC50 for rat kidney cells (NRK) was 52 microM (27 mg/l), 168 microM (90 mg/l) for A549 human lung cells, and 200 microM (108 mg/l) for Cal-62 human thyroid cells, respectively. The comparison of TBBPA with the non-brominated substance bisphenol A (BPA) clearly demonstrates that only the brominated compound exerts these effects on proliferation and cell viability. Cell cycle regulation was influenced considerably in Cal-62 cells, showing an explicit G2/M arrest in the cell cycle at TBBPA concentrations higher than 75 microM. Cellular signaling pathways directly connected to these affected parameters, e.g. the mitogen activated protein kinase (MAPK) cascades, are partly influenced in a cell specific and dose dependent manner. The extracellular-signal regulated kinase (ERK) is deactivated in NRK and A549 cells and activated in Cal-62 cells with increasing TBBPA concentrations.