nabam and Carcinoma-in-Situ

We have previously shown that a single i.p. injection of nitrosomethylurea (NMU) in 3-day-old rats orally treated with the pesticide mancozeb (MZ), the flavonoid quercetin (Q) or in combination (MZ-Q) induces hyperplasia, atypical acinar cell proliferation and carcinoma in situ (CIS) in the pancreas. This work studies the effect of oral administration of phenobarbital (PB) on this model of pancreatic carcinogenesis. The animals were fed on a diet supplemented by MZ or/and Q from the 10th day of pregnancy, thorough lactation and as pups after weaning until being sacrificed at week 24. Saline injection with non-supplemented diet was used for the control group (SAL). The experimental groups were (1) SAL (control), (2) SAL-PB, (3) NMU, (4) NMU-PB, (5) MZ-NMU, (6) MZ-NMU-PB, (7) Q-NMU, (8) Q-NMU-PB, (9) MZ-Q-NMU and (10) MZ-Q-NMU-PB. Acinar cell hyperplasia was found in all groups of NMU-treated rats. Dysplastic foci (DYS) were seen in groups 3-10 at the following percentages: 19, 48, 71, 27, 71, 35, 100 and 30, respectively. CIS were recorded in groups 4 to 10 at percentages: 4, 36, 13, 11, 0, 16, 5, respectively.. Although PB, Q or MZ given alone enhance DYS lesions in NMU-treated rats, the MZ/Q/PB combined treatments may increase (mainly in males) or decrease (mainly in female) the DYS and CIS proportion. Because PB, MZ and Q influence P450 enzymes, we suggest that these enzymes play a role in the carcinogenesis process.

Topics: Alkylating Agents; Animals; Animals, Newborn; Carcinogens; Carcinoma in Situ; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Female; Fungicides, Industrial; Hyperplasia; Maneb; Maternal Exposure; Maternal-Fetal Exchange; Methylnitrosourea; Pancreatic Neoplasms; Phenobarbital; Pregnancy; Quercetin; Rats; Rats, Wistar; Zineb

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.

Topics: Animals; Animals, Newborn; Carcinogens; Carcinoma in Situ; Cell Nucleolus; Female; Fungicides, Industrial; Hyperplasia; Lactation; Maneb; Maternal-Fetal Exchange; Methylnitrosourea; Pancreas; Pancreatic Neoplasms; Pregnancy; Rats; Rats, Wistar; Reference Values; Zineb