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<p>Rates of early-onset ischemic stroke (EOS) are rising even as incidence falls at older ages. Microplastics have recently been identified as a novel stroke risk factor, and among polymers detected in human arterial thrombi from ischemic stroke, polyamide-66 (PA66) microplastics show the highest detection frequency, with microplastic burden positively correlating with stroke severity. Here, using an integrative in silico framework, we integrate systems toxicology with multi-omics causal inference to map PA66–brain pathways in EOS. Target prediction for PA66 combined with curated stroke genes yielded 12 shared proteins enriched in platelet–endothelial and blood–brain barrier pathways. Brain protein-QTL two-sample Mendelian randomization (MR) identified 43 EOS-associated proteins (20 risk, 23 protective); intersecting with the 12 candidates prioritized a single overlap, EPHX2. Higher genetically proxied brain EPHX2 associated with lower EOS risk (odds ratio, OR 0.84; 95% CI 0.71–0.98), with the strongest signal for small-artery occlusion (OR 0.50; 0.26–0.96). Cell type–resolved sc-eQTL MR supported an astrocytic association (EPHX2 expression in astrocytes OR 0.925; 0.868–0.986; <i>P</i> = 0.016). Two-step MR implicated metabolites downstream of EPHX2—glycosyl-N-ceramide (d18:1/24:1) increased with brain EPHX2 (OR 1.205; <i>P</i> = 0.0073) and were inversely associated with EOS due to small-artery occlusion (OR 0.563; <i>P</i> = 0.049). Molecular docking placed PA66 in the canonical inhibitor pocket of soluble epoxide hydrolase, and 100-ns molecular dynamics supported a stable, pocket-bound pose. Mouse-model phenome queries for Ephx2 knockout highlighted Gene Ontology shifts in hydrolase activity, lipid metabolism and homeostasis, consistent with disrupted lipid-epoxide signaling relevant to neurovascular integrity. Single-cell RNA-seq in young-mouse stroke datasets localized Ephx2 to astrocytes and showed post-stroke downregulation. Together, these findings nominate an astrocytic EPHX2–sphingolipid axis as a plausible route by which PA66 microplastics may promote premature stroke, providing a mechanistic basis for hazard assessment and mitigation.</p>

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Polyamide-66 microplastics and early-onset ischemic stroke: a systems toxicology, multi-omics, and molecular dynamics simulation analysis

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Qiu-Han Xu,
  • Zhao-Hui Chai,
  • Jian-Cheng Jin,
  • Yu-Ning Zhang,
  • Jian Shen

摘要

Rates of early-onset ischemic stroke (EOS) are rising even as incidence falls at older ages. Microplastics have recently been identified as a novel stroke risk factor, and among polymers detected in human arterial thrombi from ischemic stroke, polyamide-66 (PA66) microplastics show the highest detection frequency, with microplastic burden positively correlating with stroke severity. Here, using an integrative in silico framework, we integrate systems toxicology with multi-omics causal inference to map PA66–brain pathways in EOS. Target prediction for PA66 combined with curated stroke genes yielded 12 shared proteins enriched in platelet–endothelial and blood–brain barrier pathways. Brain protein-QTL two-sample Mendelian randomization (MR) identified 43 EOS-associated proteins (20 risk, 23 protective); intersecting with the 12 candidates prioritized a single overlap, EPHX2. Higher genetically proxied brain EPHX2 associated with lower EOS risk (odds ratio, OR 0.84; 95% CI 0.71–0.98), with the strongest signal for small-artery occlusion (OR 0.50; 0.26–0.96). Cell type–resolved sc-eQTL MR supported an astrocytic association (EPHX2 expression in astrocytes OR 0.925; 0.868–0.986; P = 0.016). Two-step MR implicated metabolites downstream of EPHX2—glycosyl-N-ceramide (d18:1/24:1) increased with brain EPHX2 (OR 1.205; P = 0.0073) and were inversely associated with EOS due to small-artery occlusion (OR 0.563; P = 0.049). Molecular docking placed PA66 in the canonical inhibitor pocket of soluble epoxide hydrolase, and 100-ns molecular dynamics supported a stable, pocket-bound pose. Mouse-model phenome queries for Ephx2 knockout highlighted Gene Ontology shifts in hydrolase activity, lipid metabolism and homeostasis, consistent with disrupted lipid-epoxide signaling relevant to neurovascular integrity. Single-cell RNA-seq in young-mouse stroke datasets localized Ephx2 to astrocytes and showed post-stroke downregulation. Together, these findings nominate an astrocytic EPHX2–sphingolipid axis as a plausible route by which PA66 microplastics may promote premature stroke, providing a mechanistic basis for hazard assessment and mitigation.