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Bifenthrin exacerbates ulcerative colitis via immunotoxicity: network toxicology and experimental validation reveal
Lingxiao Wang1, Weixing Zhang1, Yifan Kang1
1The Colorectal Surgery Department of Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, 030012, China.
Abstract:
Bifenthrin (BF) is a widely used pyrethroid insecticide and is recognized as an endocrine-disrupting chemical (EDC). Accumulating evidence indicates that long-term exposure to BF can induce a variety of adverse health outcomes. However, its potential role in the pathogenesis of ulcerative colitis (UC) remains elusive. In this study, we integrated data from multiple databases-including the Comparative Toxicogenomics Database (CTD), TargetNet, GeneCards, SwissTargetPrediction, and STITCH-to predict potential molecular targets of BF. UC-associated genes were compiled from GeneCards, Online Mendelian Inheritance in Man (OMIM), DisGeNET, Therapeutic Target Database (TTD), and DrugBank. Candidate targets were identified by intersecting predicted BF targets with UC-related genes, followed by functional enrichment analysis using DAVID. The STRING database and Cytoscape software were employed to construct protein-protein interaction (PPI) networks and screen for hub genes. A diagnostic model based on these hub genes was established and validated using the GSE47908 and GSE13367 datasets. Additionally, immune infiltration analysis was performed to compare the UC group with controls, identifying immune cell types significantly associated with the target genes. Molecular docking simulations via AutoDock Vina were conducted to evaluate the binding affinities between BF and the five hub proteins. Functional analysis revealed that the candidate genes were primarily enriched in pathways related to oxidative stress and inflammatory responses. Five core hub genes-BCL2, TP53, TNF, IL6, and PTGS2-were consistently identified across all analytical platforms. In vitro experiments demonstrated that BF exposure significantly exacerbated colonic inflammation by downregulating anti-inflammatory/apoptotic genes (BCL2, TP53) and upregulating pro-inflammatory markers (IL6, TNF, PTGS2). Collectively, our findings suggest that bifenthrin may promote colorectal inflammation by dysregulating key genes and modulation of the pro-inflammatory immune microenvironment, thus providing novel insights into the environmental etiology of UC.
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Inflammatory Bowel Disease I: Ulcerative Colitis
Inflammatory bowel disease, or IBD, encompasses a group of disorders characterized by chronic inflammation or ulceration of the gastrointestinal tract.
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The exact cause of IBD remains unclear, although it is believed to be due to a mix of genetic, environmental, microbial, and immune factors. Genetic factors are significant in determining susceptibility to IBD, with family history being a critical risk factor. Individuals with a first-degree relative who has IBD are at...