Dysregulation of Cell Cycle Control in B6C3F1 Mice Exposed to Subchronic Ozone and 4-(N-Methyl-N-Nitrosamino)-1-(3-Pyridyl)-1-Butanone and/or Dibutyl Phthalate

This study investigates the dysregulation of cell cycle control in the lungs and livers of B6C3F1 mice exposed to ozone, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and dibutyl phthalate (DBP), both individually and in combination, over 16 and 32 weeks. We evaluated the protein expression profiles of G1/S checkpoint regulators (cyclin D1, cyclin E, PCNA), G2/M transition markers (cyclin B1, cyclin G, cyclin A), negative regulators (wild-type/mutant p53, p21, GADD45, p27), and a positive regulator (mdm2). Our findings demonstrate a pronounced upregulation in both negative (p53, p21, GADD45, p27) and positive (mdm2) regulatory proteins following exposure to the test compounds. Consequently, the G1/S transition proteins-—cyclins D1, E, and PCNA—were markedly overexpressed in the targeted tissues at both time points. Furthermore, co-exposure to two or three of these toxicants synergistically elevated the expression of cyclins D1 and E, mutant p53, and mdm2 compared to ozone treatment alone. These results suggest that the synergistic interaction of these environmental pollutants profoundly disrupts cellular checkpoints, potentially driving early tumorigenic events during subchronic exposure