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Previous research reported associations between bisphenol A (BPA) exposure and some malignant tumor incidences, yet the underlying mechanism remains largely uncertain. This investigation was aimed to explore the association of BPA exposure burden with colorectal cancer (CRC) and the role of tumor tissue lipid metabolism in the associations between BPA and CRC using lipidomic approach. Urinary BPA levels in CRC cases were significantly higher than those in controls (P value < 0.05). BPA was positively correlated with all three serum CRC biomarkers, with an estimated odds ratio (OR) of 4.45 (95% confidence interval (95% CI): [1.31, 15.14]) between the highest and lowest tertiles of exposure. Lipidomic screening of tumor samples suggested significant perturbation in the glycerophospholipid metabolism pathway, of which phosphatidylcholine (PC 34:0), phosphatidylcholine (PC 37:1), phosphatidylethanolamine (PE 34:2), triacylglycerol (TG 56:4) demonstrated mediation contribution of 21.9%, 18.7%, 18.4% and 27.39%, respectively, in the association between BPA exposure and CRC. Our work provides novel findings that cancer tissue metabolites may be playing vital mediating roles in the associations between BPA exposure burden and CRC risk. These findings contribute to better understanding of the etiology of CRC induced by environmental stressors. [Display omitted] • BPA exposure was associated with risk of CRC. • High BPA group exhibited significant lipid dysregulation in CRC tissues. • Lipid metabolites may mediate the association between BPA exposure and CRC. [ABSTRACT FROM AUTHOR]