DEHP Disrupts Lipid Metabolism Through Autophagy Hyperactivation and Mitochondrial Dysfunction [RNA-Seq]

Di(2-ethylhexyl) phthalate (DEHP) is a widely used industrial plasticizer, raising global concerns due to its potential endocrine-disrupting effects and environmental persistence. Human exposure to DEHP primarily occurs through the ingestion of contaminated food and water, inhalation of airborne particles, and dermal contact with products containing DEHP. Understanding the toxicological mechanisms of DEHP is essential for evaluating its health risks and developing effective strategies to mitigate its adverse effects. In this study, we conducted long-term exposure experiments to DEHP using both animal model and in vitro system to investigate the complex interplay among DNA methylation, hyperactivation of autophagy, mitochondrial dysfunction, and lipid accumulation induced by DEHP. The results reveal that DEHP exposure induces the degradation of DNA methyltransferase 1 (DNMT1) by enhancing its interaction with the autophagy-related protein sequestosome 1 (SQSTM1). DNMT1 degradation results in decreased methylation of the promoter regions of genes associated with autophagosome formation, subsequently increasing their expression. The resulting demethylation excessively activates autophagy, contributing to mitochondrial dysfunction and lipid accumulation in the liver. This study uncovers a previously unrecognized interplay among hyperactivation of autophagy, mitochondrial dysfunction, and lipid accumulation in the context of DEHP exposure. These findings enhance our understanding of DEHP's toxicity and underscore concerns about the long-term health effects of environmental pollutants, particularly regarding metabolic diseases.