Urban PM_0.2 Affects Astrocytes by Inducing Xenobiotic and Oxidative Stress Responses

Air pollution is the largest environmental risk factor contributing substantially to global mortality rates. Several studies demonstrated that pollutant exposure leads to neuroinflammation and oxidative stress, yet little is known about the effects induced in specific brain cell types. Here, we aimed to decipher how nanoscale particulate matter (PM_0.2, an aerodynamic diameter < 0.2 µm) collected from urban air affects a central element of the brain's homeostatic system - the astrocytes, via 24-h exposure of primary astrocyte cultures to PM_0.2 at a final concentration of 50 µg/ml. We combined transcriptomic and proteomic profiling to elucidate astrocyte-intrinsic responses to PM. PM_0.2 exposure altered the expression of 2217 mRNA, with the robust induction of xenobiotic metabolism, the Nrf2 oxidative stress response, and glutathione-mediated detoxification. Strong upregulation of cytochrome P450 genes, glutathione S-transferase superfamily, Nqo1, Ahrr and Slc17a8 was detected. Exploratory proteomic analysis identified 354 proteins with nominal evidence of altered abundance, 142 of which showed corresponding significant mRNA changes. The cross-platform-supported candidates were consistent with coordinated activation of xenobiotic-metabolism and redox-homeostasis pathways. Reanalysis of published RNA-seq datasets showed that, in contrast to PM-exposed microglia, which predominantly activate pro-inflammatory signaling pathways, astrocytes preferentially engage detoxification and antioxidant programs, while sharing a subset of stress and signaling pathways with the PM-exposed cerebral cortex in in vivo model. Our results provide insight into astrocyte-specific responses to urban air pollutant exposure and allow a better understanding of the processes activated by PM exposure in the brain.