Decabromodiphenyl ether (BDE-209) induces learning and memory impairment via JAK2/STAT3/NLRP3 axis-mediated...

Decabromodiphenyl ether (BDE-209), a brominated flame retardant widely used in electronics and construction materials, has garnered significant attention due to its environmental persistence and potential health hazards. However, research on the neurotoxic effects of flame retardants is limited, and the molecular mechanisms underlying BDE-209 neurotoxicity are not fully understood. Neuroinflammation, as a key pathway in the pathological progression of neurological disorders, has received extensive attention. This study aimed to elucidate the molecular mechanisms underlying BDE-209-induced neurotoxicity, with a specific focus on pyroptosis, a form of programmed cell death closely linked to neuroinflammation. Using both in vivo mouse models and in vitro HT22 hippocampal neuron cultures, we found that BDE-209 exposure caused significant cognitive deficits in mice and activated the classical pyroptosis pathway in the hippocampus. Further analysis revealed that BDE-209 activated the JAK2/STAT3 pathway and the NLRP3 inflammasome, triggering pyroptotic cell death in HT22 neurons. Remarkably, pharmacological inhibition of NLRP3 with MCC950 and blockade of JAK2/STAT3 signaling with AG490 significantly attenuated pyroptosis, highlighting the therapeutic potential of targeting these pathways. Collectively, our findings provide new insights into the neurotoxic effects of BDE-209, demonstrating that it induces NLRP3-mediated pyroptosis through the JAK2/STAT3 axis. This study enhances our understanding of BDE-209 neurotoxicity and highlights possible intervention strategies to mitigate its harmful effects.