Di(2-ethylhexyl) Phthalate (DEHP) Exposure Exacerbates Subarachnoid Hemorrhage by Inducing Astrocyte-Mediated Inflammation and Oxidative Stress through the ADORA1/PI3K-Akt/MAPK Axis.

Abstract

Di(2-ethylhexyl) phthalate (DEHP) is a widespread plasticizer, but its role in subarachnoid hemorrhage (SAH) remains unclear. Integrating network toxicology, machine learning, transcriptomics, immune infiltration, molecular docking/dynamics, single-cell RNA sequencing, and in vivo/ in vitro experiments, we identified 264 DEHP-SAH overlapping targets enriched in PI3K-Akt/MAPK pathways. Three core genes (ADORA1, PDGFRA, PTGS2) were screened, with ADORA1 specifically upregulated in astrocytes under SAH. Chronic DEHP exposure exacerbated neurological deficits, neuronal damage, astrocyte proliferation/activation, apoptosis, and inflammatory cytokines in SAH mice, while reducing antioxidant enzymes. In primary astrocytes, DEHP suppressed viability, activated PI3K-Akt/MAPK, and induced oxidative stress and inflammation, synergizing with Hemin. An adverse outcome pathway framework was constructed. These findings reveal that DEHP aggravates SAH neurotoxicity via ADORA1-mediated astrocyte inflammation and oxidative stress through the PI3K-Akt/MAPK axis, providing new insights into environmental pollutant neurotoxicity.