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

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.