Promoting effects of mancozeb on pancreas of nitrosomethylurea-treated rats

Rats were treated with a single i.p. injection of the carcinogen nitrosomethylurea (NMU, 50 mg/kg b.w.) at day three of age. The treatment induced hyperplastic and atypical acinar cell proliferation [focal acinar cell hyperplasia (FACH)]. In this investigation, NMU treated rats were fed AIN-76 diet containing mancozeb (MZ; 100 mg/kg diet), a polymeric complex of ethylene bis (dithiocarbamate) manganese with zinc salt, which is an agricultural fungicide.

Group one was treated with NMU plus MZ (MZ-NMU), group 2 received NMU alone (NMU), group 3 was fed MZ and saline injected (MZ-SAL) and group 4 was the saline injected control (SAL). Rats were killed at week 24 of age. In MZ-NMU group pancreas there were FACH, dysplastic foci (DYF) and carcinomas in situ (CIS). FACH were larger, coalescent and may show areas of undifferentiated cells (focus within focus). DYF contain proliferative acinar and ductular structures with loss of polarity but no malignant traits. CIS had medullary appearance or consisted of irregularly shaped acini and ducts in stromal framework. Cell had scant cytoplasm and large hyperchromatic, pleomorphic nuclei. DYF and CIS were not seen in MZ group pancreas. The MZ-NMU group had increased mitotic index and greater number of apoptotic cells. There was no pathologic change in MZ-SAL group. Our data indicated that MZ did not cause pancreatic cell proliferation in normal rats whereas it had distinct promoting and progressor effects on NMU initiated pancreatic cells. Thus, a two-stage protocol of pancreatic carcinogenesis was achieved. It is suggested that the NMU protocol may be useful for testing promoter, progressor or inhibitory effect of chemical and physical agents on cell proliferation and transformation of rat pancreas.