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  3. Mechanisms and targeted prevention of chronic pancreatitis-acinar to ductal metaplasia caused by a low concentration of di-(2-ethylhexyl)-phthalate

Mechanisms and targeted prevention of chronic pancreatitis-acinar to ductal metaplasia caused by a low concentration of di-(2-ethylhexyl)-phthalate

  • Chem Biol Interact. 2025 Sep 26:421:111758. doi: 10.1016/j.cbi.2025.111758.
Mengyue Ji 1,  Xinru Du 2,  Yue Ma 3,  Sisi Song 3,  Zhendong Wang 3,  Yancheng Gao 3,  Ye Yang 4,  Chunxiao Zhou 5,  Yuan Li 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
  • 2 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China; School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
  • 3 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China.
  • 4 The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China. Electronic address: yangye@njmu.edu.cn.
  • 5 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China. Electronic address: zhouchunxiao@njmu.edu.cn.
  • 6 Department of Gastroenterology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, Jiangsu Province, China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China; School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, Nanjing Medical University, Nanjing, 211166, Jiangsu Province, China. Electronic address: liyuan@njmu.edu.cn.
PMID: 41016453 DOI: 10.1016/j.cbi.2025.111758
Abstract

The impact of long-term exposure to low concentrations of environmental pollutants on pancreatic disorders is a major public health issue. Di-(2-ethylhexyl)-phthalate (DEHP) is a persistent environmental endocrine toxicant present in many products. Despite evidence of the harmful effects of DEHP on pancreatic tissue, the molecular mechanisms underlying its activity in chronic pancreatitis (CP) remain unclear. Acinar to ductal metaplasia (ADM) is a key pathological process in CP. Here, chronic exposure to low concentrations of DEHP elevated the expression of a glucose-regulated protein (GRP75) in mouse acinar cells. GRP75 is a bridge protein for endoplasmic reticulum (ER)-mitochondrial junctions, and the overexpression of GRP75 abnormalizes ER-mitochondrion coupling, shortening the contact distance between them. Such biological processes facilitate CA2+ release from the ER into the mitochondria and cause mitochondrial CA2+ overload, leading to the overproduction of ROS and thereby promoting the development of ADM in acinar cells. These ductal-like cells secrete Collagen and activate pancreatic stellate cells through paracrine action, synergistically promoting the development and progression of CP. Finally, we revealed that targeting GRP75 with stearic acid (SA) could prevent DEHP-induced CP-ADM via drug screening and functional analysis. Our present study offers new insights into environmental toxin-induced pancreatic disorders and suggests a potential key intervention target for the prevention of CP-ADM.

Keywords

Chronic pancreatitis-acinar to ductal metaplasia; Glucose-regulated protein 75; Molecular mechanisms; Targeted prevention; di-(2-ethylhexyl)-phthalate.

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