A combined NMR- and HPLC-MS/MS-based metabolomics to evaluate the metabolic perturbations and subacute toxic effects of endosulfan on mice

Endosulfan is the newly persistent organic pollutants (POPs) added to the Stockholm Convention as its widespread use, persistence, bioaccumulation, long-range transport, endocrine disruption, and toxicity related to various adverse effects. In the present study, male mice were administrated endosulfan at 0, 0.5, and 3.5 mg/kg by gavage for 2 weeks. ¹H-NMR-based urinary metabolomics, HPLC-MS/MS-based targeted serum metabolomics, clinical analysis, and histopathology techniques were employed to evaluate the metabolic perturbations of subacute endosulfan exposure. Endosulfan exposures resulted in weight loss, liver inflammation and necrosis, and alterations in serum amino acids and urine metabolomics. Based on altered metabolites, several significantly perturbed pathways were identified including glycine, serine, and threonine metabolism; TCA cycle; pyruvate metabolism; glycolysis or gluconeogenesis; glycerophospholipid metabolism; and glyoxylate and dicarboxylate metabolism. Such pathways were highly related to amino acid metabolism, energy metabolism, and lipid metabolism. In addition, metabolomic results also demonstrated that gut microbiota was remarkably altered after endosulfan exposure. These observations may provide novel insight into revealing the potential toxic mechanism and evaluating the health risk of endosulfan exposure at metabolomic level.