Metabolic profiling of the maternal liver in pregnant mice exposed to Di(2-ethylhexyl) phthalate (DEHP).

In this study, pregnant mice were exposed to dietary Di(2-ethylhexyl) phthalate (DEHP) (0.1 % or 0.2 %) from gestational day (GD) 0 to GD18, and maternal liver metabolomes were profiled by GC-MS/MS-based metabolomics followed by bioinformatics analysis using our PiTMaP platform. Multivariate analysis revealed clear separation between the control and DEHP groups, indicating substantial metabolic alterations in maternal liver. Among the metabolites contributing to group separation, 20 compounds, including malic acid, tryptophan, niacinamide, cysteine, and hypotaurine, showed significant differences (FDR <0.05), suggesting mitochondrial dysfunction and alterations in the tryptophan-niacinamide and hypotaurine metabolic pathways. In addition, a machine learning-based Random Forest classifier demonstrated that these significantly altered metabolites could accurately discriminate among the three groups. Further network analysis identified hypotaurine as the top network hub in the liver. These results demonstrate tissue-specific rewiring of metabolic networks under DEHP exposure, with mitochondrial and tryptophan-niacinamide pathways being prominently affected in the liver. Overall, this study provides novel mechanistic insights into maternal metabolic disturbances induced by DEHP exposure during pregnancy and contributes to the identification of organ-specific biomarkers relevant to such exposure.