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Title: Modification of N-Methyl-N-Nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid

Abstract

The effect of terephthalic acid (TPA) on urinary bladder carcinogenesis was examined. Male Wistar rats were initiated by injection of N-Methyl-N-Nitrosourea (MNU) (20 mg/kg b.w. ip) twice a week for 4 weeks, then given basal diet containing 5% TPA, 5% TPA plus 4% Sodium bicarbonate (NaHCO{sub 3}) or 1% TPA for the next 22 weeks, and then euthanized. 5% TPA treatment induced a high incidence of urinary bladder calculi and a large amount of precipitate. Though 5% TPA plus 4% Sodium bicarbonate (NaHCO{sub 3}) and 1% TPA treatment did not induce urinary bladder calculi formation, they resulted in a moderate increase in urinary precipitate. Histological examination of urinary bladder revealed that MNU-5% TPA treatment resulted in a higher incidence of simple hyperplasia, papillary or nodular hyperplasia (PN hyperplasia), papilloma and cancer than MNU control. MNU-5% TPA plus 4% Sodium bicarbonate (NaHCO{sub 3}) and 1% TPA treatment increased slightly the incidence of simple hyperplasia and PN hyperplasia (not statistically significant). The major elements of the precipitate are phosphorus, potassium, sulfur, chloride, calcium and TPA. The present study indicated that the calculi induced by TPA had a strong promoting activity on urinary bladder carcinogenesis and the precipitate containing calcium terephthalate (CaTPA) maymore » also have weak promoting activity on urinary bladder carcinogenesis.« less

Authors:
 [1];  [2];  [3];  [3];  [3];  [1];  [2];  [3];  [3];  [3];  [3];  [4]
  1. Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029 (China)
  2. (China)
  3. Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029 (China)
  4. Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029 (China) and Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029 (China). E-mail: xrwang@njmu.edu.cn
Publication Date:
OSTI Identifier:
20783396
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 210; Journal Issue: 1-2; Other Information: DOI: 10.1016/j.taap.2005.06.008; PII: S0041-008X(05)00369-8; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACID CARBONATES; BLADDER; CALCIUM; CALCULI; CARCINOGENESIS; DIET; METHYL NITROSOUREA; NEOPLASMS; PHOSPHORUS; POTASSIUM; RATS; SODIUM CARBONATES; SULFUR CHLORIDES; TEREPHTHALIC ACID

Citation Formats

Cui Lunbiao, Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029, Shi Yuan, Dai Guidong, Pan Hongxin, Chen Jianfeng, Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029, Song Ling, Wang Shouling, Chang, Hebron C., Sheng Hongbing, and Wang Xinru. Modification of N-Methyl-N-Nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid. United States: N. p., 2006. Web.
Cui Lunbiao, Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029, Shi Yuan, Dai Guidong, Pan Hongxin, Chen Jianfeng, Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029, Song Ling, Wang Shouling, Chang, Hebron C., Sheng Hongbing, & Wang Xinru. Modification of N-Methyl-N-Nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid. United States.
Cui Lunbiao, Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029, Shi Yuan, Dai Guidong, Pan Hongxin, Chen Jianfeng, Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029, Song Ling, Wang Shouling, Chang, Hebron C., Sheng Hongbing, and Wang Xinru. Sun . "Modification of N-Methyl-N-Nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid". United States. doi:.
@article{osti_20783396,
title = {Modification of N-Methyl-N-Nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid},
author = {Cui Lunbiao and Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029 and Shi Yuan and Dai Guidong and Pan Hongxin and Chen Jianfeng and Institute of Toxicology, Nanjing Medical University, 140 Han-zhong Road, Nanjing 210029 and Song Ling and Wang Shouling and Chang, Hebron C. and Sheng Hongbing and Wang Xinru},
abstractNote = {The effect of terephthalic acid (TPA) on urinary bladder carcinogenesis was examined. Male Wistar rats were initiated by injection of N-Methyl-N-Nitrosourea (MNU) (20 mg/kg b.w. ip) twice a week for 4 weeks, then given basal diet containing 5% TPA, 5% TPA plus 4% Sodium bicarbonate (NaHCO{sub 3}) or 1% TPA for the next 22 weeks, and then euthanized. 5% TPA treatment induced a high incidence of urinary bladder calculi and a large amount of precipitate. Though 5% TPA plus 4% Sodium bicarbonate (NaHCO{sub 3}) and 1% TPA treatment did not induce urinary bladder calculi formation, they resulted in a moderate increase in urinary precipitate. Histological examination of urinary bladder revealed that MNU-5% TPA treatment resulted in a higher incidence of simple hyperplasia, papillary or nodular hyperplasia (PN hyperplasia), papilloma and cancer than MNU control. MNU-5% TPA plus 4% Sodium bicarbonate (NaHCO{sub 3}) and 1% TPA treatment increased slightly the incidence of simple hyperplasia and PN hyperplasia (not statistically significant). The major elements of the precipitate are phosphorus, potassium, sulfur, chloride, calcium and TPA. The present study indicated that the calculi induced by TPA had a strong promoting activity on urinary bladder carcinogenesis and the precipitate containing calcium terephthalate (CaTPA) may also have weak promoting activity on urinary bladder carcinogenesis.},
doi = {},
journal = {Toxicology and Applied Pharmacology},
number = 1-2,
volume = 210,
place = {United States},
year = {Sun Jan 15 00:00:00 EST 2006},
month = {Sun Jan 15 00:00:00 EST 2006}
}
  • Gastric carcinoma was induced in inbred Wistar rats by p.o. administration of N-methyl-N'-nitro-N-nitrosoguanidine for 25 weeks, and cell proliferation and growth of the gastric carcinoma in an incipient stage were studied. A microscopic cancer was found by 24 weeks, and macroscopic cancers were found after 27 weeks. All the cancers were a single lesion located at the midpoint of the lesser curvature of the stomach. Histologically, they were tubular adenocarcinomas. The mucosal changes predisposing to the development of carcinomas were focal erosions and dysplasias confined to the midpoint of the lesser curvature. The malignant transformation appeared to occur in themore » dysplastic cells of the eroded mucosa by 17 to 18 weeks after N-methyl-N'-nitro-N-nitrosoguanidine treatment. Following the malignant change, the labeling indices of the tissues with (/sup 3/H)thymidine decreased, suggesting an elongation of cell cycle time. By repeated injections of (/sup 3/H)thymidine, a time required for all the cancer cells to enter S phase (reflecting the maximum cell cycle time) was estimated to be about 3.5 days. This gave a theoretical doubling time for the gastric cancers. On the other hand, from the temporal observations of tumor volumes, it was shown that the gastric cancers in an incipient stage underwent exponential growth with a doubling time of 14 days. The difference between the theoretical and actual doubling time might reflect a cell loss rate in the cancer tissue.« less
  • A single dose of N-methyl-N-nitrosourea given to sexually immature female Buf/N rats produces a high incidence of mammary adenocarcinomas. A large percentage of these tumors contain the Ha-ras oncogene, activated by a G {yields} A transition at the second nucleotide of codon 12. Copenhagen rats, on the other hand, are completely resistant to mammary tumor induction by a number of carcinogens, including N-methyl-N-nitrosourea. Here the authors show, using a sensitive method involving PCR, that codon 12 Ha-ras mutations occur in the mammary glands of both Buf/N and Copenhagen rats 30 days after N-methyl-N-nitrosourea treatment. These mutations were evenly distributed amongmore » individual mammary glands and were present in purified mammary epithelial cells. In Buf/N rats, the fraction of cells containing a mutated Ha-ras allele increased by a factor of 10-100 between 30 and 60 days, whereas in Copenhagen rats, there was no such increase during this time period. They conclude that the resistance of the Copenhagen rat to mammary carcinogenesis is not due to a defect in initiation but rather appears to be due to the inability of cells containing a mutated ras allele to undergo sustained clonal expansion.« less
  • An investigation of N-methyl-N'-(..beta..-D-xyloxyl)urea (I) and its nitroso derivative (II) has been carried out in the MINDO/3 approximation by the MO-LCAO method. It has been shown that the very significant difference between the energies of molecule I in the free state and in a crystal is due to the potential energy of the crystal field and intermolecular hydrogen bonds. An analysis of the distribution of the charges on the atoms showed that the most probably site for protonation and nucleophilic attack in I and II is the carbonyl group. A picture of the changes in the electronic structure and propertiesmore » of the reaction centers in I and II under model acid-base catalysis conditions has been obtained.« less
  • N-Methyl-N-nitrosourea (MNU) is a reactive, mutagenic methylating agent. MNU methylates DNA at various sites, including guanine N{sup 7}, guanine O{sup 6}, and adenine N{sup 3}. Dixit and Gold ((1986) Proc. Natl, Acad. Sci. U.S.A. 83, 8039-8043) reported that ellagic acid, a phenolic natural product, inhibited the mutagenicity of MNU in Salmonella typhimurium strain TA 100, inhibited salmon sperm DNA alkylation by ({sup 3}H)MNU, and also greatly reduced the ratio of guanine O{sup 6} to guanine N{sup 7} alkylation. We have examined the MNU-induced alkylation of calf thymus DNA and evaluated the effect of ellagic acid on this binding. Ellagic acidmore » had only a slight effect on total alkylation and did not alter the ratio of methylation at guanine-O{sup 6} and -N{sup 7} positions. In further experiments, ellagic acid did not significantly inhibit MNU mutagenicity. These findings do not support the potential use of ellagic acid as an inhibitor of biological damage induced by nitrosoureas.« less
  • Dideoxy chain-termination DNA sequencing was used to determine the specific DNA base changes induced after in vivo exposure of Escherichia coli to N-methyl-N-nitrosourea (MNU) and N-ethyl-N-nitrosourea (ENU) using the xanthine guanine phosphoribosyltransferase (gpt) gene as the genetic target. The resultant mutation spectra were compared with the levels of O/sup 6/-alkylguanine and O/sup 4/-alkylthymidine in genomic DNA immediately after exposure. All (39/39) of the MNU-induced mutations were G x C ..-->.. A x T transition. In contrast, 24/33 point mutations isolated following ENU treatment were G x C ..-->.. A x T transitions, 7/33 were A x T ..-->.. G xmore » C transitions, 1/33 was a G x C ..-->.. C x G transversion, and 1/33 was an A x T ..-->.. C x G transversion. Three large insertions, probably of spontaneous origin, were also isolated. O/sup 4/-alkylthymidine/O/sup 6/-alkylguanine ratios were 0.014 for MNU and 0.28 for ENU. These data suggest that the difference in the mutation spectrum of MNU versus ENU may be attributed, in part, to the different ratio of O/sup 6/-alkylguanine versus O/sup 4/-alkylthymidine produced in the DNA. Of the G x C ..-->.. A x T transitions, 82% of the MNU- and 71% of the ENU-induced mutations occurred at the middle guanine of the sequence 5'-GG(A or T)-3'.« less