Chronic Styrene Exposure Causes Oxidative Stress, Neuroinflammation, and Hippocampal Memory Dysfunction via NLRP3 Inflammasome Activation

Several studies focused on the molecular mechanisms linking oxidative stress and inflammation, due to their crucial role in different pathological conditions, including neurodegenerative disorders. Here, we studied the link between redox unbalance and neuroinflammation in a model of styrene-induced toxicity in the hippocampus. We used a rat model of chronic styrene exposure to assess its impact on hippocampal function. Behavioral tests were performed to evaluate recognition and spatial memory. Molecular and histological analyses were carried out to measure ROS production, inflammatory markers (COX-2, TNF-α, IL-1β), and immunoreactivity for IBA-1 and GFAP. Synaptic alterations, activation of pro-apoptotic pathways, and NLRP3 inflammasome levels were also evaluated. We found that toxic exposure to styrene can affect both recognition and spatial memory by causing functional, morphological, and molecular alterations in the hippocampus. Indeed, we observed increased ROS production and elevated levels of inflammatory markers, as well as increased IBA-1 and GFAP immunoreactivity, suggesting an activation of the immune system with the involvement of microglia and astrocytes in the hippocampus of styrene-treated animals. These findings were associated with molecular and structural synaptic alterations and activation of pro-apoptotic pathways. Moreover, we pointed out the possible involvement of inflammasome activation in mediating oxidative-inflammatory damage, and we documented an increased level of NLRP3 inflammasome after styrene exposure. Our data provide novel experimental evidence of styrene-induced memory dysfunctions, demonstrating that exposure to this toxic compound can impinge on the hippocampus through a mechanism involving the ROS-driven inflammation, activating the NLRP3 inflammasome axis. From a translation point of view, our results indicate that styrene exposure can be a high-risk factor for developing cognitive deficits and suggest considering the ROS/NLRP3 pathway as a target to prevent/attenuate neurotoxicity.