Metabolome-wide association study of serum exogenous chemical residues in a cohort with 5 major chronic diseases

Chronic diseases have become main killers affecting the health of human, and environmental pollution is a major health risk factor that cannot be ignored. It has been reported that exogenous chemical residues including pesticides, herbicides, fungicides, veterinary drugs and persistent organic pollutants are associated with chronic diseases. However, the evidence for their relationship is equivocal and the underlying mechanisms are unclear.We aim to investigate the linkages between serum exogenous chemical residues and 5 main chronic diseases including obesity, hyperuricemia, hypertension, diabetes and dyslipidemia, and further reveal the metabolic perturbations of chronic diseases related to exogenous chemical residue exposure, then gain potential mechanism insight at the metabolic level.LC-MS-based targeted and nontargeted methods were respectively performed to quantify exogenous chemical residues and acquire metabolic profiling of 496 serum samples from chronic disease patients. Non-parametric test, correlation and regression analyses were carried out to investigate the association between exogenous chemical residues and chronic diseases. Metabolome-wide association study combined with the meeting-in-the-middle strategy and mediation analysis was performed to reveal and explain exposure-related metabolic disturbances and their risk to chronic diseases.In the association analysis of 106 serum exogenous chemical residues and 5 chronic diseases, positive associations of serum perfluoroalkyl substances (PFASs) with hyperuricemia were discovered while other associations were not significant. 240 exposure markers of PFASs and 84 disease markers of hyperuricemia were found, and 47 of them were overlapped and considered as putative effective markers. Serum uric acid, amino acids, cholesterol, carnitines, fatty acids, glycerides, glycerophospholipids, ceramides, and a part of sphingolipids were positively correlated with PFASs and associated with increased risk for hyperuricemia. Creatine, creatinine, glyceryl monooleate, phosphatidylcholine 36:6, phosphatidylethanolamine 40:6, cholesterol and sphingolipid 36:1;2O were significant markers which mediated the associations of the residues with hyperuricemia.Our study demonstrated a significantly positive association between PFASs exposure and hyperuricemia. The most significant metabolic abnormality was lipid metabolism which not only was positively associated with PFASs, but also increased the risk of hyperuricemia.