Exploring the mechanism of 6PPD/6PPD-Q-induced allergic rhinitis based on network toxicology, molecular docking, and molecular dynamic simulation

Abstract

Abstract N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) and its ozonated derivative, 6PPD-quinone (6PPD-Q), are tire-derived contaminants with established aquatic toxicity, yet their role in respiratory allergies like Allergic Rhinitis (AR) remains unclear. This study employs an integrative computational approach combining toxicological profiling, network pharmacology, and molecular dynamics (MD) simulations to elucidate their allergenic mechanisms. Potential targets were identified from multiple databases and intersected with AR-associated genes. Toxicological modeling revealed that both compounds pose significant respiratory and cutaneous sensitization risks, with 6PPD-Q exhibiting notable genotoxicity. Network analysis prioritized PTPRC (CD45), CXCL8, CCL2, TNF, and AKT1 as central hub targets. Functional enrichment indicated that these pollutants may disrupt leukocyte chemotaxis and activate key inflammatory pathways, including IL-17, NF-kappa B, and Fc epsilon RI signaling. MD simulations suggested stable binding of both pollutants within the PTPRC active site; notably, 6PPD-Q was associated with more pronounced conformational changes in the receptor, suggesting a potential for stronger immunomodulatory effects that warrants experimental investigation. This study provides mechanistic insight offers computational insights into how 6PPD and 6PPD-Q could contribute to mucosal immune dysregulation and may promote AR pathogenesis through multi-target actions, providing a preliminary foundation for environmental risk assessment and safer tire additive design.