Pre-existing liver dysfunction modulates di-(2-ethylhexyl) phthalate (DEHP)-associated biological responses through host-microbiome networks.

Pre-existing metabolic conditions may profoundly alter biological responses to environmental pollutants, yet this dimension remains underexplored in environmental health. This study examined whether pre-existing metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with altered biological responses to di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer. In a human cohort, fatty liver status was associated with altered urinary DEHP metabolite profiles, characterized by a higher proportion of the bioactive mono-(2-ethylhexyl) phthalate, suggesting disease-associated differences in DEHP biotransformation. Using a rat model and multi-omics approaches, we observed that hepatic lipid accumulation was associated with higher systemic DEHP burden and altered tissue distribution, with increased accumulation in the liver and intestine. Under this dual stress, DEHP exposure was associated with perturbations in key metabolic pathways, including amino acid, lipid, and drug metabolism. Transcriptomic analysis revealed upregulation of genes involved in fatty acid synthesis and cholesterol metabolism, consistent with enhanced hepatic lipogenesis. Concurrently, gut microbiota dysbiosis intensified, characterized by shifts in microbial community composition, including reduced Firmicutes and Bacteroidota and altered genus-level taxa linked to host metabolic and inflammatory responses. Integrative multi-omics analysis indicated possible coordinated alterations across the microbiome, metabolome, and hepatic transcriptome, potentially involving lipid metabolism and inflammatory signaling pathways. Taken together, these findings suggest that pre-existing MASLD may exacerbate DEHP-associated biological responses through pathways involving the gut-liver axis, highlighting host metabolic status as an important consideration in interpreting chemical-associated biological responses.