High cytotoxicity of a degraded TBBPA, dibromobisphenol A, through apoptotic and necrosis pathways.

Halogenated flame retardants comprising bisphenol A (BPA) derivatives, such as tetrabromobisphenol A (TBBPA), have been studied their adverse effects on human health. However, despite the fact that these halogenated BPAs are easily degraded in the environment, the risks to living organisms due to these degraded products have mostly been overlooked. To evaluate the potential toxicity of degraded TBBPAs and related compounds, we examined the cytotoxicity of halogenated bisphenol A derivatives possessing one to four halogen atoms in vitro. The results indicated that the degraded TBBPA derivatives exhibited strong cytotoxicity against HeLa cells than TBBPA. Interestingly, the di-halogenated BPA derivatives possessing two halogen atoms exhibited the strongest cytotoxicity among tested compounds. In addition, a lactate dehydrogenase release assay, fluorescence spectroscopy and flow cytometry results indicated that dibromo-BPA and diiodo-BPA induced both apoptotic and necrotic cell death by damaging the cell membranes of HeLa cells. Moreover, Escherichia coli growth was inhibited in the presence of dehalogenated TBBPA and related compounds. These findings suggest that halogenated BPA derivatives that leak from various flame-retardant-containing products require strict monitoring, as not only TBBPA but also its degraded products in environment can exert adverse effects to human health.

Evaluation of the Influence of Halogenation on the Binding of Bisphenol A to the Estrogen-Related Receptor γ.

Halogenation of organic compounds is one the most important transformations in chemical synthesis and is used for the production of various industrial products. A variety of halogenated bisphenol analogs have recently been developed and are used as alternatives to bisphenol A (BPA), which is a raw material of polycarbonate that has adverse effects in animals. However, limited information is available on the potential toxicity of the halogenated BPA analogs. In the present study, to assess the latent toxicity of halogenated BPA analogs, we evaluated the binding and transcriptional activities of halogenated BPA analogs to the estrogen-related receptor γ (ERRγ), a nuclear receptor that contributes to the growth of nerves and sexual glands. Fluorinated BPA analogs demonstrated strong ERRγ binding potency, and inverse antagonistic activity, similar to BPA. X-ray crystallography and fragment molecular orbital (FMO) calculation revealed that a fluorine-substituted BPA analog could interact with several amino acid residues of ERRγ-LBD, strengthening the binding affinity of the analogs. The ERRγ binding affinity and transcriptional activity of the halogenated BPAs decreased with the increase in the size and number of halogen atom(s). The IC50 values, determined by the competitive binding assay, correlated well with the binding energy obtained from the docking calculation, suggesting that the docking calculation could correctly estimate the ERRγ binding potency of the BPA analogs. These results confirmed that ERRγ has a ligand binding pocket that fits very well to BPA. Furthermore, this study showed that the binding affinity of the BPA analogs can be predicted by the docking calculation, indicating the importance of the calculation method in the risk assessment of halogenated compounds.