PCB-118 increases PDE4D abundance and thermal stability in bladder cancer cells: An integrative toxicogenomic and cellular study

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants with potential carcinogenic effects, but their molecular associations with bladder cancer remain poorly understood. Here, we integrated toxicogenomic, transcriptomic, single-cell, structural, and cellular analyses to identify candidate proteins responsive to PCB-118 in bladder cancer. Differentially expressed genes and weighted gene co-expression network modules derived from GSE13507 were integrated with curated PCB-associated genes, followed by random forest and least absolute shrinkage and selection operator analyses. PDE4D, SH2D3C, and NRG1 were consistently prioritized and showed concordant expression patterns in an independent cohort. Single-cell transcriptomic analyses revealed distinct expression distributions across tumor-associated stromal, endothelial, epithelial, and immune cell populations. Molecular docking predicted favorable interactions between PCB-118 and all three candidate proteins, with PDE4D showing the lowest binding energy. During 100-ns molecular dynamics simulations, the PCB-118-PDE4D complex exhibited the most stable and compact structural behavior. In T24 bladder cancer cells, exposure to PCB-118 at 5-20 nM increased PDE4D protein abundance. An exploratory cellular thermal shift assay showed an apparent increase in PDE4D thermal stability following PCB-118 treatment, providing preliminary support for a possible interaction at the cellular level. These findings identify PDE4D as a candidate PCB-118-responsive protein in bladder cancer cells and provide a basis for investigating its functional contribution to PCB-associated cellular effects.