Network toxicology and experimental validation reveal TDCPP as an emerging environmental risk factor for chronic kidney disease

Plain Language Summary Background: Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a widely used organophosphorus flame retardant that has raised growing concern because it is persistent, can bioaccumulate, and is toxic. However, its possible role in chronic kidney disease (CKD) is still not well understood. Methods: We used network toxicology, molecular docking, transcriptomic validation, and mouse exposure experiments to uncover the mechanisms linking TDCPP exposure to kidney injury. Results: We found 1270 overlapping targets between predicted TDCPP-binding proteins and CKD-related genes. Enrichment analyses showed strong links to inflammatory and apoptotic processes, as well as key signaling pathways including PI3K–Akt, MAPK, Ras, and cAMP. Machine learning methods (LASSO, SVM-RFE, RF) identified two hub genes, CTRB1 and HSPA1A , which were both significantly downregulated in CKD transcriptomes and showed perfect diagnostic performance (AUC = 1.0). Immune cell analysis showed that CKD tissues had increased regulatory T cells, monocytes, M2 macrophages, and neutrophils, and CTRB1 / HSPA1A expression was correlated with specific immune cell subsets. Molecular docking predicted favorable binding of TDCPP to both proteins, with the strongest affinity for CTRB1 (–7.2 kcal/mol). In vivo , TDCPP exposure caused dose-dependent tubular degeneration, inflammation, and increased serum BUN and creatinine, along with marked downregulation of CTRB1 and HSPA1A . Conclusion: Taken together, these findings suggest that TDCPP may contribute to CKD by disrupting CTRB1 / HSPA1A and activating PI3K–Akt/MAPK signaling, which leads to immune dysregulation and progressive kidney injury. We propose a new adverse outcome pathway (AOP) framework linking TDCPP exposure to CKD, and highlight CTRB1 and HSPA1A as potential biomarkers and mechanistic targets for environmental nephrotoxicity. Plain Language Summary This study explores how the flame retardant TDCPP might contribute to chronic kidney disease (CKD). Researchers used various methods, including network toxicology and mouse experiments, to identify 1270 targets shared between TDCPP-binding proteins and CKD-related genes. They found that TDCPP affects inflammatory and apoptotic processes and key signaling pathways. Two genes, CTRB1 and HSPA1A, were identified as crucial, showing strong links to immune cell changes in CKD. TDCPP binds well to these proteins, especially CTRB1, and exposure in mice led to kidney damage and inflammation. The study suggests TDCPP disrupts these genes, contributing to CKD, and proposes them as biomarkers for environmental nephrotoxicity. Text is machine generated and may contain inaccuracies. FAQ