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

Jiaxin Li; Hong Zhang; Xi Li; Kexin Chen; Yushan Wu; Mingshan Jiang; Zhen Zeng; Chunxiang Ma; Fang Yin; Yan Li; Jiangmei Pang; Hao Lin; Jingjing Chen; Minghua Lv; Zou Xiang; Hu Zhang

doi:10.1016/j.freeradbiomed.2025.07.018

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

Free Radic Biol Med. 2025 Jul 11:S0891-5849(25)00822-6. doi: 10.1016/j.freeradbiomed.2025.07.018. Online ahead of print.

Authors

Jiaxin Li¹, Hong Zhang², Xi Li¹, Kexin Chen¹, Yushan Wu¹, Mingshan Jiang¹, Zhen Zeng¹, Chunxiang Ma¹, Fang Yin¹, Yan Li¹, Jiangmei Pang¹, Hao Lin¹, Jingjing Chen¹, Minghua Lv¹, Zou Xiang³, Hu Zhang⁴

Affiliations

¹ Department of Gastroenterology and Lab of inflammatory Bowel Disease and Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China.
² Department of Gastroenterology and Lab of inflammatory Bowel Disease and Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Gastroenterology, Affiliated Hospital of North Sichuan Medical College&Sichuan Branch of National Clinical Research Center for Digestive Diseases, Nanchong, Sichuan 637000, China.
³ Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong.
⁴ Department of Gastroenterology and Lab of inflammatory Bowel Disease and Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: zhanghu@scu.edu.cn.

PMID: 40653097
DOI: 10.1016/j.freeradbiomed.2025.07.018

Abstract

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, 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. Mendelian randomization (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 the 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.

Keywords: Inflammatory bowel disease; Mendelian randomization; Mono(2-ethylhexyl) phthalate; National Health and Nutrition Examination Survey; Network toxicology.