Mixed PAEs Induce Hepatotoxicity in Cyprinus carpio via Oxidative Stress and Metabolic Disorders: Insights from Machine Learning and Multi-Omics
Typical phthalate esters (PAEs), including diisobutyl phthalate (DiBP), dibutyl phthalate (DBP), and di(2-ethylhexyl) phthalate (DEHP), are common plasticizers widely present in aquatic environments, posing potential ecological risks. However, PAEs commonly occur as complex mixtures in aquatic systems, and the hepatic responses and underlying molecular alterations induced by combined PAEs exposure remain insufficiently characterized. In this study, carp (Cyprinus carpio) was used as a model organism to investigate sublethal ecotoxicological effects of mixed DiBP, DBP, and DEHP exposure. By integrating machine learning with multi-omics analyses (metabolomics, proteomics, transcriptomics), we characterized hepatic injury, metabolic pathway disruptions, and gene/protein expression alterations, validated by biological assays (biochemical measurements, histopathology, ultrastructural observations, TUNEL staining). Results show mixed PAEs exposure significantly disturbed glutathione, Peroxisome Proliferator-Activated Receptor (PPAR), arachidonic acid, and linoleic acid metabolism, causing redox imbalance, lipid peroxidation, and mitochondrial dysfunction; dysregulated pathway interactions further enhanced oxidative damage and apoptosis, impairing hepatic detoxification and energy homeostasis. This study provides mechanistic insights into mixed PAEs toxicity and contributes to a better understanding of the ecological impacts of coexisting pollutants in aquatic environments.