Exogenous chemical exposures and metabolic disruptions in hyperuricemia: a multi-omics mediation study

BACKGROUND: Hyperuricemia has emerged as a significant public health concern. However, the relationship between hyperuricemia and both individual and mixed exogenous chemicals remains poorly understood, and the underlying mechanisms are still unclear. OBJECTIVES: This study aimed to elucidate the risk factors and biological mechanisms underlying hyperuricemia by integrating multi-omics data. METHODS: UPLC-MS-based methods were employed to quantify 186 exogenous chemicals and profile metabolites from serum samples of 298 pairs of hyperuricemia patients and matched control subjects. RESULTS: Significant disturbances in amino acid metabolism, energy metabolism, and gut microbiota-related metabolism were observed in hyperuricemia patients. The concentrations of perfluoroheptanoic acid, perfluorobutanesulfonate, sodium 4-chlorophenoxyacetate, and indole-3-butyric acid were significantly higher in hyperuricemia patients. A positive association was observed between combined exposures and hyperuricemia risk, with indole-3-butyric acid being the most significant contributor. Perfluorinated compounds may affect uric acid excretion via gut microbiome-related metabolites. Indole-3-butyric acid might modulate the enzymatic activity of various acyl-CoA dehydrogenases, leading to disruptions in fatty acid metabolism and an increased risk of hyperuricemia. Furthermore, genetic susceptibility appears to further increase the risk of hyperuricemia. CONCLUSIONS: In summary, hyperuricemia is related to the interplay of environmental exposures and individual genetic susceptibility, with metabolic dysregulation serving as a crucial mediating link. These findings offer novel insights into the potential health risks associated with exogenous chemical exposures.