Mechanisms underlying DEHP/MEHP-induced toxicity in multiple sclerosis: An integrated analysis combining network toxicology, bioinformatics, and in vivo experimental validation

Abstract

Di(2-ethylhexyl) phthalate (DEHP) and its key bioactive metabolite, mono(2-ethylhexyl) phthalate (MEHP), can readily cross the blood-brain barrier, affecting the central nervous system and promoting demyelination. Therefore, DEHP and MEHP may contribute to inflammatory demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms remain incompletely elucidated. This study aimed to explore these potential mechanisms through network toxicology, bioinformatics, and in vivo experimental validation. We identified 103 MEHP-targeted proteins implicated in MS pathogenesis, which were primarily involved in inflammatory and immune-related pathways, such as the IL-17 signaling pathway. Topological analysis of the protein-protein interaction network identified five key targets: CTNNB1, IL1B, BCL2, MMP9, and ALB. Among these, CTNNB1, IL1B, and MMP9 formed a robust diagnostic model for MS, with their expression associated with immune cell infiltration. Molecular docking revealed strong affinities between MEHP and the key targets, while molecular dynamics simulations confirmed stable MEHP-IL1B interactions. In vivo experiments demonstrated that DEHP exposure reduced body weight, promoted inflammation and spinal cord demyelination, and increased IL-1β expression. This study identifies IL1B as a high-affinity MEHP target and provides a mechanistic framework linking DEHP/MEHP exposure to autoimmune demyelinating pathology.

Keywords: Molecular docking; Molecular dynamics simulation; Mono(2-ethylhexyl) phthalate; Multiple sclerosis; Network toxicology.