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

Abstract

The brominated flame retardant tetrabromobisphenol A (TBBPA) has recognized neurotoxic properties mediated by intracellular Ca²⁺ imbalance and oxidative stress. Although these factors are known to trigger the release of Zn²⁺ from intracellular stores, the effects of TBBPA on Zn²⁺ homeostasis in neurons and the role of Zn²⁺in 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 Zn²⁺ from the intracellular stores and increases its intracellular concentration, followed by Zn²⁺ displacement from the cells. TBBPA-evoked Zn²⁺ transients are partially mediated by Ca²⁺ and ROS. Application of TPEN, Zn²⁺ chelator, potentiates TBBPA- and glutamate-induced ⁴⁵Ca 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 Zn²⁺. 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 Zn²⁺ homeostasis in neuronal cultures, and we revealed complex roles for endogenous Zn²⁺ in cytoprotection and TBBPA toxicity in cultured neurons.

Keywords: CGC; NMDA receptor; Neuroprotection; Neurotoxicity; Oxidative stress; TBBPA.