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Inhibition by Ethinylestradiol of N-Ethyl-N-Nitrosourea-Initiated Uterine Carcinogenesis in Transgenic Mice Carrying a Human Prototype C-Ha-ras Gene (rasH2 Mice)

Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu, Tokyo 183-8509, Japan

Yoko Kashida

Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu, Tokyo 183-8509, Japan

Makoto Ueda

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Hiroshi Onodera

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Tamotsu Takizawa

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Masao Hirose

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Kunitoshi Mitsumori

Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8, Saiwai-cho, Fuchu, Tokyo 183-8509, Japan, mitsumor@ cc.tuat.ac.jp

In order to demonstrate the tumor promoting effect of ethinylestradiol (EE) in our uterine carcinogenesis model, rasH2 or ICR mice given an intraperitoneal injection of 120 mg/kg body weight of N-ethyl-N-nitrosourea (ENU) or an intra-uterine injection of 50 mg/kg body weight of ENU, respectively, followed by 2.5 or 0 ppm EE in the diet for 24 weeks in experiment 1 and 6 weeks in experiment 2. In experiment 1, in ICR mice, the incidences of adenocarcinomas in the ENU alone and the ENU+EE groups were 0% and 37.5%, respectively, the difference being statistically significant. The incidences of atypical hyperplasias and endometrial hyperplasias in the ENU+EE group were also significantly higher than those in the ENU alone group. In rasH2 mice, on the other hand, no endometrial proliferative lesions were induced in the uterus of the ENU+EE group, although uterine adenocarcinomas (55.6%), atypical hyperplasias (33.3%), and endometrial hyperplasias (22.2%) were observed in the ENU alone group. Proliferating cell nuclear antigen (PCNA) positive indices for uterine adenocarcinomas and atypical hyperplasias in ICR mice treated with ENU+EE showed high values, but those in rasH2 mice given ENU alone were comparable to data for intact epithelium. In experiment 2, the immunohistochemical expression of estrogen receptor (ER) in the uterine luminal and glandular epithelium in the ENU+EE group of ICR mice was moderate to marked, but that in the ENU alone group was slight. There was no consistent difference in ER expression in the uterine luminal and glandular epithelium between ENU+EE and ENU alone groups of rasH2 mice. These results suggest that 2.5 ppm EE paradoxically inhibits the uterine carcinogenesis in rasH2 mice initiated with ENU.

Key Words: rasH2 mice • N-ethyl-N-nitrosourea • estrogen • uterine carcinogenesis.

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Toxicologic Pathology, Vol. 31, No. 5, 496-505 (2003)
DOI: 10.1080/01926230390226014


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Watanabe, T. Articles by Mitsumori, K. Search for Related Content PubMed PubMed Citation Articles by Watanabe, T. Articles by Mitsumori, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ETHINYLESTRADIOL N-NITROSO-N-ETHYLUREA Medline Plus Health Information Uterine Cancer Social Bookmarking                         What's this?