Multidimensional Deciphering Underlying Effects of PFOA Exposure in Ulcerative Colitis: From Epidemiological Insights to Toxicological Mechanisms

Abstract

Perfluorooctanoic acid (PFOA), a representative persistent organic pollutant (POP), has been linked to numerous adverse health effects. Ulcerative colitis (UC), characterized by recurrent colon inflammation, is known to have environmental exposure as a primary etiological factor; however, the toxicological mechanisms underlying PFOA-induced UC remain unclear. This study therefore aims to comprehensively investigate the association between PFOA exposure and UC. A meta-analysis was conducted to evaluate the association between PFOA exposure and UC onset, and network toxicology, cross-species transcriptomics, protein–protein interaction networks, and weighted gene coexpression network analysis were employed to identify potential targets and mechanisms. Single-cell RNA sequencing, molecular docking, and Mendelian randomization were used to pinpoint and validate hub genes, while in vivo DSS-induced colitis and in vitro inflammation models were applied to assess the functional impact of PFOA. The meta-analysis of four studies confirmed a significant positive association between PFOA exposure and UC risk (Fisher z = 0.20, 95% CI: 0.13–0.27). We identified 170 overlapping targets linking PFOA to UC, predominantly enriched in immune-inflammatory activation and metabolic disruption. Seven hub genes (IRF1, CXCL1, CXCL9, CXCL10, CXCL11, CASP1, and IL1B) constituted a UC-associated coexpression module, with monocytes/macrophages as primary sources by single-cell profiling. Molecular docking confirmed PFOA binding to these proteins, and Mendelian randomization established IRF1 as a causal risk factor. In vivo, PFOA exacerbated DSS-induced colitis, impairing barrier function, promoting apoptosis and mitochondrial dysfunction. In conclusion, PFOA exposure is associated with increased UC risk and may promote colonic inflammation by affecting the chemokine–inflammasome network and epithelial function. IRF1 may be a key hub in this process, but its upstream role needs validation. These findings highlight the potential importance of reducing environmental pollutant exposure in UC prevention.