Combining epidemiology, network toxicology and in vivo experimental validation to uncover takeout-mediated DEHP/MEHP toxicity in inflammatory bowel disease.

Background And Aims: Mono (2-ethylhexyl) phthalate (MEHP), the active metabolite of di-(2-ethylhexyl) phthalate (DEHP), is a widely used plasticizer in food packaging materials. While DEHP/MEHP has been linked to various health risks, the underlying mechanisms between DEHP/MEHP exposure and inflammatory bowel disease (IBD) remain poorly understood. This study aims to explore this relationship using a comprehensive approach integrating epidemiology, Mendelian randomization (MR), network toxicology, and animal experiments.

Methods: Using data from the National Health and Nutrition Examination Survey (NHANES), we first assessed the association between takeout frequency and MEHP exposure among 17,859 participants. MR analysis was employed to evaluate the relationship between MEHP exposure and IBD risk using large-scale genome-wide association studies (GWAS). To elucidate the molecular mechanisms, network toxicology was employed to identify key molecular targets and pathways. The roles of hub genes were validated in vitro cell line experiments and molecular docking based on public databases. Additionally, our study assessed the direct impact of DEHP/MEHP exposure on colitis phenotypes in mice.

Results: Our analysis demonstrated that individuals who consumed takeout more than 7 times per week exhibited significantly higher urinary MEHP levels (β = 2.06, 95 % CI: 1.06-3.06; p < 0.001). MR analysis indicated that MEHP exposure increased the risk of IBD (OR = 1.08, 95 % CI: 1.011-1.163; p = 0.024). Through network toxicology, we identified IL-1β, MMP9, and PPARG as central mediators of MEHP-induced intestinal barrier disruption and immune dysregulation, with their roles confirmed via public transcriptomic data and in vitro validation. Molecular docking further substantiated strong binding interactions between MEHP and these protein targets. Our experiments also confirmed that DEHP exposure had a detrimental impact on the colon of mice, resulting in weight loss, colon length reduction, inflammation increase, and histopathological changes.

Conclusions: Collectively, our findings establish the correlation between dietary DEHP/MEHP exposure and IBD and reveal the potential mechanism of DEHP-induced colitis.