NBT-T2

MOCA Induces Mitosis Across Mammalian Bladder Cell Lines Independent of Metabolic Activation

4,4'-Methylenebis(2-chloroaniline) (MOCA), a Group 1 carcinogen, is linked to bladder cancer across species, yet its mechanism remains unclear. While hepatic N-acetyltransferase (NAT) metabolism is traditionally implicated, dogs lack NAT but still develop bladder cancer, suggesting an alternative, metabolism-independent pathway. Kobayashi et al. investigated whether MOCA universally induces mitotic progression in mammalian bladder cells.

They analyzed human (T24, 5637), mouse (MBT-2), and rat (NBT-T2) bladder carcinoma cell lines. MOCA treatment significantly increased the proportion of cells in the M phase compared to control and other aromatic amines, with consistent effects observed even at concentrations as low as 4 µM (Control vs. 4 µM MOCA: p< 0.0001; Fig. 1A-C, F). Co-treatment with rat liver S9 metabolic activation system significantly suppressed MOCA-induced M phase entry (MOCA vs. MOCA+S9: p< 0.0477; Fig. 1D-E), indicating that metabolic processing reduces MOCA's mitotic activity. While S9 alone variably affected baseline mitosis depending on the cell line, the suppressive effect on MOCA was consistent.

These findings demonstrate that MOCA directly induces mitotic progression in mammalian bladder cells across species at environmentally relevant concentrations. The suppression of this effect by metabolic enzymes supports a model wherein parent MOCA, rather than its metabolites, drives chromosomal instability via aberrant mitosis, providing a unifying mechanism for its cross-species carcinogenicity.