Tetrabromobisphenol A disturbs zinc homeostasis in cultured cerebellar granule cells: A dual role in neurotoxicity.

The brominated flame retardant tetrabromobisphenol A (TBBPA) has recognized neurotoxic properties mediated by intracellular Ca imbalance and oxidative stress. Although these factors are known to trigger the release of Zn from intracellular stores, the effects of TBBPA on Zn homeostasis in neurons and the role of Znin TBBPA neurotoxicity have not yet been studied. Therefore, we investigated zinc transients in primary cultures of rat cerebellar granule cells and assessed their involvement in TBBPA neurotoxicity. The results demonstrate that TBBPA releases Zn from the intracellular stores and increases its intracellular concentration, followed by Zn displacement from the cells. TBBPA-evoked Zn transients are partially mediated by Ca and ROS. Application of TPEN, Zn chelator, potentiates TBBPA- and glutamate-induced Ca uptake, enhances TBBPA-induced ROS production and potentiates decreases in the ΔΨm in cells treated with 25 μM TBBPA, revealing the potential neuroprotective capacity of endogenous Zn. However, the administration of TPEN does not aggravate TBBPA neurotoxicity, and even slightly decreases neuronal death induced by 25 μM TBBPA. In summary, it was shown for the first time that TBBPA interferes with the cellular Zn homeostasis in neuronal cultures, and we revealed complex roles for endogenous Zn in cytoprotection and TBBPA toxicity in cultured neurons.