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

• Published in: Food and chemical toxicology 2017-11, Vol.109 (Pt 1), p.363-375
• Main Authors: Zieminska, Elzbieta, Ruszczynska, Anna, Lazarewicz, Jerzy W.
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Cell Death - drug effects; Cells, Cultured; Cerebellum - cytology; Cerebellum - drug effects; Cerebellum - metabolism; CGC; Female; Flame Retardants - toxicity; Homeostasis - drug effects; Male; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neurotoxicity; NMDA receptor; Oxidative stress; Oxidative Stress - drug effects; Polybrominated Biphenyls - toxicity; Rats; Rats, Wistar; Reactive Oxygen Species - metabolism; TBBPA
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2017.09.021

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. •TBBPA interferes with the cellular Zn2+ homeostasis in neuronal cultures.•TBBPA-evoked Zn2+ transients are partially mediated by Ca2+ and ROS.•TPEN, Zn2+ chelator, potentiates TBBPA- and glutamate-induced 45Ca uptake.•TPEN enhances TBBPA-induced ROS production and potentiates decreases in the ΔΨm.•TPEN does not aggravate TBBPA neurotoxicity.