BBP acts as an exogenous modulator of MMP9 to rewire vascular immunity and promote atherosclerosis.
TL;DR
Findings suggest that BBP exposure is associated with alterations in vascular inflammatory processes involving MMP9 and CXCR2, and provides evidence supporting an inflammatory recruitment mechanism involving MMP9 and CXCR2 in BBP-associated vascular responses and offers a framework for future investigation into the contribution of environmental pollutants to atherosclerosis.
Abstract
Environmental exposure to endocrine-disrupting chemicals has been increasingly implicated in cardiovascular disease, yet the causal molecular mechanisms linking such exposures to atherosclerosis remain incompletely defined. Benzyl butyl phthalate (BBP), a widely used plasticizer, has been associated with vascular dysfunction, but its mechanistic contribution to atherogenesis is unclear. Here, we employed an integrative systems biology framework combining network toxicology, transcriptomic profiling, protein-protein interaction network analysis, molecular docking, molecular dynamics simulations, and summary-data-based Mendelian randomization to systematically elucidate BBP-associated atherosclerotic mechanisms. A total of 114 overlapping targets were identified between BBP-related and atherosclerosis-associated datasets, with MMP9 emerging as a central hub across network topology, transcriptomic validation, and structural analyses. Molecular docking and molecular dynamics simulations demonstrated stable and high-affinity binding between BBP and MMP9, supporting the concept that BBP may act as an exogenous modulator of protease function. Functional enrichment and gene set enrichment analyses consistently revealed immune activation and leukocyte recruitment as dominant biological processes across independent datasets. Furthermore, Mendelian randomization analysis provided genetic evidence supporting causal involvement of immune-related genes, particularly CXCR2, a key regulator of leukocyte trafficking. Integrative multi-level evidence and functional in vitro assays point toward an MMP9-associated, CXCR2-related inflammatory recruitment mechanism, in which BBP-induced modulation of MMP9 may alter chemokine processing, which subsequently enhances neutrophil chemotaxis and potentially contributes to vascular inflammation and atherosclerosis. Collectively, these findings suggest that BBP exposure is associated with alterations in vascular inflammatory processes involving MMP9 and CXCR2. By integrating computational analyses with experimental validation, our study provides evidence supporting an inflammatory recruitment mechanism involving MMP9 and CXCR2 in BBP-associated vascular responses and offers a framework for future investigation into the contribution of environmental pollutants to atherosclerosis.